diff --git a/src/wp-includes/media.php b/src/wp-includes/media.php
index 4cd69ade6cbb7..70756fa4a9acf 100644
--- a/src/wp-includes/media.php
+++ b/src/wp-includes/media.php
@@ -6885,9 +6885,9 @@ function wp_get_media_library_upload_settings(): array {
  * browser honors Document-Isolation-Policy: without isolation the page never
  * becomes cross-origin isolated, the script would no-op, and the whole
  * wp-upload-media dependency chain would be loaded for nothing. The same
- * goes for a screen wp_set_up_cross_origin_isolation() did not isolate,
- * such as the Customizer or the Site Icon picker: the media frame loads
- * there too, but its uploads stay on the classic path.
+ * goes for a screen wp_send_document_isolation_policy_header() did not
+ * isolate, such as the Customizer or the Site Icon picker: the media frame
+ * loads there too, but its uploads stay on the classic path.
  *
  * The screen script self-guards at runtime too: when the browser turns out
  * not to be isolated or lacks client-side media support, it no-ops and the
@@ -6945,7 +6945,8 @@ function _wp_enqueue_media_upload_pipeline_script( string $handle ): void {
  * Covers every `wp.media` frame that uploads through `wp.Uploader`: the
  * Media Library grid and the media modal the block editor, the site editor
  * and the block widgets screen open. wp_enqueue_media() calls this on any
- * screen that was cross-origin isolated, so it rarely needs calling directly.
+ * screen wp_send_document_isolation_policy_header() isolated, so it rarely
+ * needs calling directly.
  *
  * @since 7.2.0
  */
@@ -6972,6 +6973,9 @@ function wp_enqueue_media_new_upload(): void {
  * Forcing `crossorigin="anonymous"` would turn those into CORS requests
  * and break any resource served without `Access-Control-Allow-Origin`.
  *
+ * Sending the header also opts the screen's media frames into client-side
+ * uploads, so call this before wp_enqueue_media() runs.
+ *
  * @since 7.2.0
  *
  * @global bool $_wp_cross_origin_isolated Whether the Document-Isolation-Policy header was sent.
@@ -6996,14 +7000,15 @@ function wp_send_document_isolation_policy_header(): bool {
 /**
  * Whether the current request has been set up for cross-origin isolation.
  *
- * True once wp_set_up_cross_origin_isolation() has sent the
+ * True once wp_send_document_isolation_policy_header() has sent the
  * Document-Isolation-Policy header for the screen being rendered, which is
  * what lets scripts that need a cross-origin isolated page, such as the
  * client-side media upload integration, decide whether to load at all.
  *
- * A plugin can isolate a screen on its own by sending the header directly,
- * as the Gutenberg plugin does on the block editor screens, so a header
- * already queued for the response counts too.
+ * A header a plugin sends itself does not count, since the plugin may
+ * isolate its screen for reasons of its own. To run the client-side
+ * pipeline on a screen core does not isolate, call
+ * wp_send_document_isolation_policy_header() before wp_enqueue_media().
  *
  * @since 7.2.0
  *
@@ -7014,13 +7019,6 @@ function wp_send_document_isolation_policy_header(): bool {
 function wp_is_cross_origin_isolated_request(): bool {
 	global $_wp_cross_origin_isolated;
 
-	if ( true === $_wp_cross_origin_isolated ) {
-		return true;
-	}
-
-	return array_any(
-		headers_list(),
-		fn( $header ) => 0 === stripos( $header, 'Document-Isolation-Policy:' )
-	);
+	return true === $_wp_cross_origin_isolated;
 }
 
diff --git a/tests/phpunit/tests/media/wpCrossOriginIsolation.php b/tests/phpunit/tests/media/wpCrossOriginIsolation.php
index 64884b4e284f9..3722e1618a482 100644
--- a/tests/phpunit/tests/media/wpCrossOriginIsolation.php
+++ b/tests/phpunit/tests/media/wpCrossOriginIsolation.php
@@ -6,6 +6,7 @@
  * @group media
  * @covers ::wp_set_up_cross_origin_isolation
  * @covers ::wp_send_document_isolation_policy_header
+ * @covers ::wp_is_cross_origin_isolated_request
  * @covers ::wp_is_client_side_media_processing_enabled
  */
 class Tests_Media_wpCrossOriginIsolation extends WP_UnitTestCase {
@@ -121,6 +122,32 @@ public function test_sends_header_for_chrome_137() {
 		$this->assertTrue( wp_send_document_isolation_policy_header(), 'The Document-Isolation-Policy header should be sent for Chrome 137.' );
 	}
 
+	/**
+	 * @ticket 66490
+	 *
+	 * @runInSeparateProcess
+	 * @preserveGlobalState disabled
+	 */
+	public function test_sending_header_marks_request_isolated(): void {
+		$_SERVER['HTTP_USER_AGENT'] = 'Mozilla/5.0 (Windows NT 10.0; Win64; x64) AppleWebKit/537.36 (KHTML, like Gecko) Chrome/137.0.0.0 Safari/537.36';
+
+		$this->assertFalse( wp_is_cross_origin_isolated_request(), 'The request should not be isolated before the header is sent.' );
+
+		wp_send_document_isolation_policy_header();
+
+		$this->assertTrue( wp_is_cross_origin_isolated_request(), 'The request should be isolated once core sends the header.' );
+	}
+
+	/**
+	 * @ticket 66490
+	 */
+	public function test_request_not_isolated_when_header_not_sent(): void {
+		$_SERVER['HTTP_USER_AGENT'] = 'Mozilla/5.0 (Windows NT 10.0; rv:128.0) Gecko/20100101 Firefox/128.0';
+
+		$this->assertFalse( wp_send_document_isolation_policy_header() );
+		$this->assertFalse( wp_is_cross_origin_isolated_request(), 'The request should not be isolated when the header was not sent.' );
+	}
+
 	/**
 	 * @ticket 64766
 	 */
diff --git a/tests/phpunit/tests/media/wpEnqueueMediaFrameUpload.php b/tests/phpunit/tests/media/wpEnqueueMediaFrameUpload.php
index 0b6a917e324ed..81f049fbd601c 100644
--- a/tests/phpunit/tests/media/wpEnqueueMediaFrameUpload.php
+++ b/tests/phpunit/tests/media/wpEnqueueMediaFrameUpload.php
@@ -56,7 +56,7 @@ public function set_up() {
 		$this->original_wp_scripts = $wp_scripts;
 		$wp_scripts                = new WP_Scripts();
 
-		// The screen was cross-origin isolated, as wp_set_up_cross_origin_isolation() records.
+		// The screen was cross-origin isolated, as wp_send_document_isolation_policy_header() records.
 		$GLOBALS['_wp_cross_origin_isolated'] = true;
 	}
 
@@ -91,9 +91,9 @@ public function test_script_enqueued() {
 	}
 
 	/**
-	 * A screen wp_set_up_cross_origin_isolation() did not isolate cannot run
-	 * the pipeline, so the media frame there keeps its classic uploads and
-	 * does not download the pipeline bundles.
+	 * A screen wp_send_document_isolation_policy_header() did not isolate
+	 * cannot run the pipeline, so the media frame there keeps its classic
+	 * uploads and does not download the pipeline bundles.
 	 *
 	 * @ticket 65661
 	 */
diff --git a/tests/phpunit/tests/media/wpEnqueueMediaNewUpload.php b/tests/phpunit/tests/media/wpEnqueueMediaNewUpload.php
index 02d00b730c79d..afa75cf4fc12d 100644
--- a/tests/phpunit/tests/media/wpEnqueueMediaNewUpload.php
+++ b/tests/phpunit/tests/media/wpEnqueueMediaNewUpload.php
@@ -54,7 +54,7 @@ public function set_up() {
 		$this->original_wp_scripts = $wp_scripts;
 		$wp_scripts                = new WP_Scripts();
 
-		// The screen was cross-origin isolated, as wp_set_up_cross_origin_isolation() records.
+		// The screen was cross-origin isolated, as wp_send_document_isolation_policy_header() records.
 		$GLOBALS['_wp_cross_origin_isolated'] = true;
 	}