diff --git a/dev-packages/e2e-tests/test-applications/tsx-express/package.json b/dev-packages/e2e-tests/test-applications/tsx-express/package.json
index 6659dbcfc603..df56af29737e 100644
--- a/dev-packages/e2e-tests/test-applications/tsx-express/package.json
+++ b/dev-packages/e2e-tests/test-applications/tsx-express/package.json
@@ -27,7 +27,6 @@
     "tsx": "^4.20.3"
   },
   "volta": {
-    "node": "20.19.5",
     "extends": "../../package.json"
   }
 }
diff --git a/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario-reload.mjs b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario-reload.mjs
new file mode 100644
index 000000000000..07e8afb65e04
--- /dev/null
+++ b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario-reload.mjs
@@ -0,0 +1,28 @@
+import * as Sentry from '@sentry/node';
+import { tracingChannel } from 'node:diagnostics_channel';
+import { createRequire } from 'node:module';
+
+Sentry.init({ tracesSampleRate: 0 });
+
+let loads = 0;
+let injections = 0;
+Sentry.getClient().on('orchestrion.module-injected', moduleName => {
+  if (moduleName === 'dataloader') {
+    injections++;
+  }
+});
+tracingChannel('orchestrion:dataloader:load').start.subscribe(() => {
+  loads++;
+});
+
+const url = import.meta.resolve('dataloader');
+await import(`${url}?first`);
+await import(`${url}?second`);
+
+const require = createRequire(import.meta.url);
+delete require.cache[require.resolve('dataloader')];
+injections = 0;
+
+const DataLoader = require('dataloader');
+const value = await new DataLoader(async keys => keys).load('real-key');
+process.stdout.write(JSON.stringify([{ value, loads, injections }]));
diff --git a/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario.cjs b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario.cjs
new file mode 100644
index 000000000000..7f567101fd87
--- /dev/null
+++ b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario.cjs
@@ -0,0 +1,29 @@
+const Sentry = require('@sentry/node');
+const { tracingChannel } = require('node:diagnostics_channel');
+
+Sentry.init({ tracesSampleRate: 0 });
+
+let loads = 0;
+let injections = 0;
+Sentry.getClient().on('orchestrion.module-injected', moduleName => {
+  if (moduleName === 'dataloader') {
+    injections++;
+  }
+});
+tracingChannel('orchestrion:dataloader:load').start.subscribe(() => {
+  loads++;
+});
+
+async function run() {
+  const observations = [];
+  for (let attempt = 0; attempt < 2; attempt++) {
+    const DataLoader = require('dataloader');
+    const value = await new DataLoader(async keys => keys).load('real-key');
+    observations.push({ value, loads, injections });
+    delete require.cache[require.resolve('dataloader')];
+  }
+  await Sentry.close(1000);
+  process.stdout.write(JSON.stringify(observations));
+}
+
+run();
diff --git a/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario.mjs b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario.mjs
new file mode 100644
index 000000000000..58772fbed931
--- /dev/null
+++ b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/scenario.mjs
@@ -0,0 +1,22 @@
+import * as Sentry from '@sentry/node';
+import { tracingChannel } from 'node:diagnostics_channel';
+
+Sentry.init({ tracesSampleRate: 0 });
+
+let loads = 0;
+let injections = 0;
+Sentry.getClient().on('orchestrion.module-injected', moduleName => {
+  if (moduleName === 'dataloader') {
+    injections++;
+  }
+});
+tracingChannel('orchestrion:dataloader:load').start.subscribe(() => {
+  loads++;
+});
+
+const { default: DataLoader } = await import(
+  `${import.meta.resolve('dataloader')}${process.argv[2] ?? '?instrumentation-test'}`
+);
+const value = await new DataLoader(async keys => keys).load('real-key');
+await Sentry.close(1000);
+process.stdout.write(JSON.stringify([{ value, loads, injections }]));
diff --git a/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/test.ts b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/test.ts
new file mode 100644
index 000000000000..09bbe2b284b1
--- /dev/null
+++ b/dev-packages/node-integration-tests/suites/tracing/orchestrion-tsx/test.ts
@@ -0,0 +1,49 @@
+import { spawnSync } from 'node:child_process';
+import { join } from 'node:path';
+import { expect, test } from 'vitest';
+
+test.each([
+  { name: 'plain Node CommonJS', flags: [], scenario: 'scenario.cjs', operations: 2 },
+  { name: 'tsx CommonJS', flags: ['--require', 'tsx/cjs'], scenario: 'scenario.cjs', operations: 2 },
+  { name: 'plain Node ESM', flags: [], scenario: 'scenario.mjs', operations: 1 },
+  // tsx can replace the hook's source, requiring another transform before compilation.
+  {
+    name: 'tsx ESM',
+    flags: ['--import', 'tsx'],
+    scenario: 'scenario.mjs',
+    operations: 1,
+    injections: expect.any(Number),
+  },
+  {
+    name: 'plain Node ESM fragment',
+    flags: [],
+    scenario: 'scenario.mjs',
+    operations: 1,
+    suffix: '#instrumentation-test',
+  },
+  {
+    name: 'tsx ESM fragment',
+    flags: ['--import', 'tsx'],
+    scenario: 'scenario.mjs',
+    operations: 1,
+    suffix: '#instrumentation-test',
+    injections: expect.any(Number),
+  },
+  { name: 'plain Node after queried imports', flags: [], scenario: 'scenario-reload.mjs', operations: 1 },
+  { name: 'tsx after queried imports', flags: ['--import', 'tsx'], scenario: 'scenario-reload.mjs', operations: 1 },
+])('instruments each operation exactly once with $name', ({ flags, scenario, operations, suffix, injections }) => {
+  const result = spawnSync(process.execPath, [...flags, join(__dirname, scenario), suffix ?? '?instrumentation-test'], {
+    encoding: 'utf8',
+    timeout: 30_000,
+  });
+
+  expect(result.error).toBeUndefined();
+  expect(result.status, result.stderr).toBe(0);
+  expect(JSON.parse(result.stdout)).toEqual(
+    Array.from({ length: operations }, (_, index) => ({
+      value: 'real-key',
+      loads: index + 1,
+      injections: injections ?? index + 1,
+    })),
+  );
+});
diff --git a/packages/server-runtime-injection/src/register.ts b/packages/server-runtime-injection/src/register.ts
index fd9289aeb26d..4b51eea9a053 100644
--- a/packages/server-runtime-injection/src/register.ts
+++ b/packages/server-runtime-injection/src/register.ts
@@ -1,4 +1,5 @@
 import { consoleSandbox, debug, getClient, GLOBAL_OBJ, parseSemver } from '@sentry/core';
+import { createHash } from 'node:crypto';
 import { existsSync, readFileSync } from 'node:fs';
 import * as Module from 'node:module';
 import { dirname, join } from 'node:path';
@@ -10,6 +11,11 @@ import { initialize, load, resolve, createDiagnosticsPort } from '@apm-js-collab
 import { setDiagnosticsHook } from '@apm-js-collab/tracing-hooks/lib/diagnostics.js';
 
 type NodeModule = {
+  Module: {
+    prototype: {
+      _compile: (this: unknown, content: string, filename: string, ...args: unknown[]) => unknown;
+    };
+  };
   registerHooks?: (options: { load: Function; resolve: Function }) => { deregister: () => void };
   register?: typeof register;
 };
@@ -192,7 +198,7 @@ export function registerDiagnosticsChannelInjection(): void {
 
   // `Module.registerHooks` / `Module.register` are newer than the @types/node
   // we build against, hence the cast.
-  const mod = Module as NodeModule;
+  const mod = Module as unknown as NodeModule;
 
   setDiagnosticsHook(({ url, moduleName, error }): void => {
     if (error) {
@@ -224,7 +230,42 @@ export function registerDiagnosticsChannelInjection(): void {
   try {
     if (typeof mod.registerHooks === 'function' && stableSyncHooks) {
       initialize({ instrumentations: SENTRY_RUNTIME_INSTRUMENTATIONS });
-      mod.registerHooks({ resolve, load: globalAny.Deno ? withDenoFormats(load) : load });
+      const filesLoadedByHook = new Map<string, string>();
+      const loadHook = globalAny.Deno ? withDenoFormats(load) : load;
+      mod.registerHooks({
+        resolve,
+        load: (url: string, context: { format?: string }, nextLoad: Function) => {
+          const result = loadHook(url, context, nextLoad) as
+            | { format?: string; source?: string | Uint8Array; shortCircuit?: boolean }
+            | undefined;
+          const format = result?.format ?? context.format;
+          if (
+            (format == null || format === 'commonjs') &&
+            result?.shortCircuit === true &&
+            result?.source != null &&
+            url.startsWith('file:')
+          ) {
+            const sourceHash = createHash('sha256').update(result.source).digest('hex');
+            filesLoadedByHook.set(pathToFileURL(fileURLToPath(url)).href, sourceHash);
+          }
+          return result;
+        },
+      });
+
+      // Custom require hooks bypass load. Avoid transforming files twice when load already handled them.
+      const prototype = mod.Module.prototype;
+      const originalCompile = prototype._compile;
+      new ModulePatch({ instrumentations: SENTRY_RUNTIME_INSTRUMENTATIONS }).patch();
+      const patchedCompile = prototype._compile;
+      prototype._compile = function (content, filename, ...args) {
+        const url = pathToFileURL(filename).href;
+        const loadedSourceHash = filesLoadedByHook.get(url);
+        filesLoadedByHook.delete(url);
+        const alreadyTransformed =
+          loadedSourceHash !== undefined && loadedSourceHash === createHash('sha256').update(content).digest('hex');
+        const compile = alreadyTransformed ? originalCompile : patchedCompile;
+        return compile.call(this, content, filename, ...args);
+      };
       debug.log('Registered diagnostics-channel injection via Module.registerHooks()');
     } else if (typeof mod.register === 'function' && !globalAny.Bun && !globalAny.Deno) {
       // `Module.register` + the `_compile` patch is Node 18.19–24.12 / 25.0
diff --git a/packages/server-runtime-injection/test/register.test.ts b/packages/server-runtime-injection/test/register.test.ts
index f34408f98009..3dfa3bdb4b15 100644
--- a/packages/server-runtime-injection/test/register.test.ts
+++ b/packages/server-runtime-injection/test/register.test.ts
@@ -15,10 +15,12 @@ type LoadHook = (url: string, context: unknown, nextLoad: (url: string, context:
 // the real `Module.registerHooks({ resolve, load })` with the mocked (undefined-returning) callbacks,
 // leaving a broken resolve hook installed process-wide that crashes vitest's next dynamic `import()`.
 const registerHooksMock = vi.fn<(options: { load: LoadHook; resolve: unknown }) => void>();
+const modulePrototypeMock = vi.hoisted(() => ({ _compile: vi.fn() }));
 vi.mock('node:module', async importOriginal => {
   const actual = await importOriginal<typeof NodeModule>();
   return {
     ...actual,
+    Module: { prototype: modulePrototypeMock },
     registerHooks: (options: { load: LoadHook; resolve: unknown }) => registerHooksMock(options),
     register: vi.fn(),
   };
@@ -81,6 +83,7 @@ describe('registerDiagnosticsChannelInjection - bundled/tree-shaken detection',
   }
 
   beforeEach(async () => {
+    modulePrototypeMock._compile = vi.fn();
     delete GLOBAL_OBJ.__SENTRY_ORCHESTRION__;
     setDiagnosticsHookMock.mockClear();
     warnSpy = vi.spyOn(console, 'warn').mockImplementation(() => undefined);
@@ -93,9 +96,19 @@ describe('registerDiagnosticsChannelInjection - bundled/tree-shaken detection',
 
   afterEach(() => {
     delete GLOBAL_OBJ.__SENTRY_ORCHESTRION__;
+    vi.unstubAllGlobals();
     warnSpy.mockRestore();
   });
 
+  it('installs the CommonJS compiler fallback on Deno', () => {
+    vi.stubGlobal('Deno', { version: { deno: '2.8.3' } });
+    const originalCompile = modulePrototypeMock._compile;
+
+    registerDiagnosticsChannelInjection();
+
+    expect(modulePrototypeMock._compile).not.toBe(originalCompile);
+  });
+
   it('includes the underlying error when registering the hooks fails', () => {
     // Deno always takes the `Module.registerHooks` path, independent of the Node version running the tests.
     (globalThis as { Deno?: unknown }).Deno = { version: { deno: '2.8.3' } };