diff --git a/src/wp-includes/formatting.php b/src/wp-includes/formatting.php
index 462ebaf1f4..dc4bf24648 100644
--- a/src/wp-includes/formatting.php
+++ b/src/wp-includes/formatting.php
@@ -3065,6 +3065,11 @@ function wp_targeted_link_rel_callback( $matches ) {
 	 */
 	$rel = apply_filters( 'wp_targeted_link_rel', 'noopener noreferrer', $link_html );
 
+	// Avoid additional regex if the filter removes rel values.
+	if ( ! $rel ) {
+		return "<a $link_html>";
+	}
+
 	// Value with delimiters, spaces around are optional.
 	$attr_regex = '|rel\s*=\s*?(\\\\{0,1}["\'])(.*?)\\1|i';
 	preg_match( $attr_regex, $link_html, $rel_match );
diff --git a/tests/phpunit/tests/formatting/WPTargetedLinkRel.php b/tests/phpunit/tests/formatting/WPTargetedLinkRel.php
index 49c843ec2c..5693f02973 100644
--- a/tests/phpunit/tests/formatting/WPTargetedLinkRel.php
+++ b/tests/phpunit/tests/formatting/WPTargetedLinkRel.php
@@ -71,4 +71,16 @@ class Tests_Targeted_Link_Rel extends WP_UnitTestCase {
 		$expected = '<p>Links: <a href="/" target="_blank" rel="noopener noreferrer">Change me</a> <a href="/">Do not change me</a></p>';
 		$this->assertEquals( $expected, wp_targeted_link_rel( $content ) );
 	}
+
+	/**
+	 * Ensure empty rel attributes are not added.
+	 *
+	 * @ticket 45352.
+	 */
+	public function test_ignore_if_wp_targeted_link_rel_nulled() {
+		add_filter( 'wp_targeted_link_rel', '__return_empty_string' );
+		$content  = '<p>Links: <a href="/" target="_blank">Do not change me</a></p>';
+		$expected = '<p>Links: <a href="/" target="_blank">Do not change me</a></p>';
+		$this->assertEquals( $expected, wp_targeted_link_rel( $content ) );
+	}
 }