diff --git a/.changeset/item-click-foreign-targets.md b/.changeset/item-click-foreign-targets.md
new file mode 100644
index 0000000000000..3e6ef72165910
--- /dev/null
+++ b/.changeset/item-click-foreign-targets.md
@@ -0,0 +1,6 @@
+---
+'@astryxdesign/core': patch
+---
+
+[fix] A clickable Item or ListItem (one with `onClick` and no `role`) no longer runs it for a click that belongs to something else: a click inside content the caller portals out of the row with its own `createPortal`, or on a role-based control (`role="tab"`, `"switch"`, `"menuitem"` and the rest of the shared interactive list) nested in the row. (#8977)
+@HelloOjasMutreja
diff --git a/packages/core/src/Item/Item.test.tsx b/packages/core/src/Item/Item.test.tsx
index a36e05f5de792..5cdc72ac44542 100644
--- a/packages/core/src/Item/Item.test.tsx
+++ b/packages/core/src/Item/Item.test.tsx
@@ -10,6 +10,7 @@
  */
 
 import {Activity, use, useRef, type ReactNode} from 'react';
+import {createPortal} from 'react-dom';
 import {
   afterEach,
   beforeAll,
@@ -1967,3 +1968,90 @@ describe('Item empty slots', () => {
     expect(screen.getAllByText('0')).toHaveLength(3);
   });
 });
+
+describe('Item row onClick: clicks that belong to something else', () => {
+  it('runs for a click on the row itself', async () => {
+    const user = userEvent.setup();
+    const onClick = vi.fn();
+    render(<Item label="Invoice 42" onClick={onClick} />);
+    await user.click(screen.getByText('Invoice 42'));
+    expect(onClick).toHaveBeenCalledTimes(1);
+  });
+
+  it('does not run for a click inside a portal rendered from the row', async () => {
+    const user = userEvent.setup();
+    const onClick = vi.fn();
+    const onPortalClick = vi.fn();
+    render(
+      <Item
+        label="Invoice 42"
+        onClick={onClick}
+        endContent={createPortal(
+          <div data-testid="portal-content" onClick={onPortalClick}>
+            Edit
+          </div>,
+          document.body,
+        )}
+      />,
+    );
+    await user.click(screen.getByTestId('portal-content'));
+    expect(onPortalClick).toHaveBeenCalledTimes(1);
+    expect(onClick).not.toHaveBeenCalled();
+  });
+
+  it.each(['tab', 'switch', 'menuitem', 'checkbox', 'option'])(
+    'does not run for a click on a role="%s" control in endContent',
+    async role => {
+      const user = userEvent.setup();
+      const onClick = vi.fn();
+      render(
+        <Item
+          label="Invoice 42"
+          onClick={onClick}
+          endContent={
+            <div role={role} tabIndex={0} data-testid="control">
+              Control
+            </div>
+          }
+        />,
+      );
+      await user.click(screen.getByTestId('control'));
+      expect(onClick).not.toHaveBeenCalled();
+    },
+  );
+
+  it('does not run for a click on a read-only native input in endContent', async () => {
+    const user = userEvent.setup();
+    const onClick = vi.fn();
+    render(
+      <Item
+        label="Invoice 42"
+        onClick={onClick}
+        endContent={
+          <input
+            type="checkbox"
+            aria-readonly="true"
+            aria-label="Paid"
+            readOnly
+          />
+        }
+      />,
+    );
+    await user.click(screen.getByRole('checkbox', {name: 'Paid'}));
+    expect(onClick).not.toHaveBeenCalled();
+  });
+
+  it('does not run for a click on a native control in endContent', async () => {
+    const user = userEvent.setup();
+    const onClick = vi.fn();
+    render(
+      <Item
+        label="Invoice 42"
+        onClick={onClick}
+        endContent={<button type="button">Action</button>}
+      />,
+    );
+    await user.click(screen.getByRole('button', {name: 'Action'}));
+    expect(onClick).not.toHaveBeenCalled();
+  });
+});
diff --git a/packages/core/src/Item/Item.tsx b/packages/core/src/Item/Item.tsx
index 7867977d2cf7a..d9271a458dfb1 100644
--- a/packages/core/src/Item/Item.tsx
+++ b/packages/core/src/Item/Item.tsx
@@ -61,6 +61,7 @@ import {computeTargetAndRel} from '../Link/computeTargetAndRel';
 import {useLinkComponent} from '../Link/useLinkComponent';
 import {
   cancelNestedTouchPress,
+  hasInteractiveAncestor,
   PRESSABLE_CONTAINER_ATTRIBUTE,
   useClickableContainerProxy,
 } from '../hooks/useClickableContainer';
@@ -825,7 +826,16 @@ export function Item({
       return;
     }
     const target = e.target as HTMLElement;
-    if (target.closest('button, a, input, select, textarea')) {
+    if (
+      // React bubbles a click through a portal the caller renders from the
+      // row (its own `createPortal`), but its target is not in the row.
+      !e.currentTarget.contains(target) ||
+      // A native control owns the click, as it always has (this also keeps a
+      // read-only input and a row inside a link or button inert).
+      target.closest('button, a, input, select, textarea') ||
+      // So does a nested role-based control (role="tab", role="switch").
+      hasInteractiveAncestor(target, e.currentTarget)
+    ) {
       return;
     }
     if (isLinkRow) {