diff --git a/src/wp-admin/options.php b/src/wp-admin/options.php
index b45cbb00387ce..2c16b6930a23a 100644
--- a/src/wp-admin/options.php
+++ b/src/wp-admin/options.php
@@ -267,16 +267,41 @@
 
 	if ( 'general' === $option_page ) {
 		// Handle custom date/time formats.
+		$invalid_date_time_format = false;
+
 		if ( ! empty( $_POST['date_format'] ) && isset( $_POST['date_format_custom'] )
 			&& '\c\u\s\t\o\m' === wp_unslash( $_POST['date_format'] )
 		) {
-			$_POST['date_format'] = $_POST['date_format_custom'];
+			$date_format_custom = trim( wp_unslash( $_POST['date_format_custom'] ) );
+
+			if ( '' === $date_format_custom ) {
+				$_POST['date_format']     = get_option( 'date_format' );
+				$invalid_date_time_format = true;
+			} else {
+				$_POST['date_format'] = $date_format_custom;
+			}
 		}
 
 		if ( ! empty( $_POST['time_format'] ) && isset( $_POST['time_format_custom'] )
 			&& '\c\u\s\t\o\m' === wp_unslash( $_POST['time_format'] )
 		) {
-			$_POST['time_format'] = $_POST['time_format_custom'];
+			$time_format_custom = trim( wp_unslash( $_POST['time_format_custom'] ) );
+
+			if ( '' === $time_format_custom ) {
+				$_POST['time_format']     = get_option( 'time_format' );
+				$invalid_date_time_format = true;
+			} else {
+				$_POST['time_format'] = $time_format_custom;
+			}
+		}
+
+		if ( $invalid_date_time_format ) {
+			add_settings_error(
+				'general',
+				'invalid_date_time_format',
+				__( 'Please configure a valid date and time format.' ),
+				'error'
+			);
 		}
 
 		// Map UTC+- timezones to gmt_offsets and set timezone_string to empty.
diff --git a/src/wp-includes/formatting.php b/src/wp-includes/formatting.php
index 498d676f5c20f..761306ff90c0c 100644
--- a/src/wp-includes/formatting.php
+++ b/src/wp-includes/formatting.php
@@ -4957,6 +4957,10 @@ function sanitize_option( $option, $value ) {
 			} else {
 				$value = strip_tags( $value );
 				$value = wp_kses_data( $value );
+
+				if ( ( 'date_format' === $option || 'time_format' === $option ) && '' === $value ) {
+					$error = __( 'Please configure a valid date and time format.' );
+				}
 			}
 			break;
 
diff --git a/tests/phpunit/tests/option/sanitizeOption.php b/tests/phpunit/tests/option/sanitizeOption.php
index 68597b8acdaea..deaf2c170721a 100644
--- a/tests/phpunit/tests/option/sanitizeOption.php
+++ b/tests/phpunit/tests/option/sanitizeOption.php
@@ -175,4 +175,43 @@ public function data_sanitize_option_permalink_structure() {
 			array( new WP_Error( 'wpdb_get_table_charset_failure' ), false, false ), // @ticket 53986
 		);
 	}
+
+	/**
+	 * @ticket 65281
+	 *
+	 * @covers ::sanitize_option
+	 * @covers ::get_settings_errors
+	 *
+	 * @dataProvider data_sanitize_option_date_time_format
+	 */
+	public function test_sanitize_option_date_time_format( $option_name, $provided, $expected, $valid ) {
+		global $wp_settings_errors;
+
+		$old_wp_settings_errors = (array) $wp_settings_errors;
+
+		update_option( $option_name, $expected );
+
+		$actual = sanitize_option( $option_name, $provided );
+		$errors = get_settings_errors( $option_name );
+
+		$wp_settings_errors = $old_wp_settings_errors;
+
+		if ( $valid ) {
+			$this->assertEmpty( $errors );
+		} else {
+			$this->assertNotEmpty( $errors );
+			$this->assertSame( 'invalid_' . $option_name, $errors[0]['code'] );
+		}
+
+		$this->assertSame( $expected, $actual );
+	}
+
+	public function data_sanitize_option_date_time_format() {
+		return array(
+			array( 'date_format', 'F j, Y', 'F j, Y', true ),
+			array( 'date_format', '', 'Y-m-d', false ),
+			array( 'time_format', 'g:i a', 'g:i a', true ),
+			array( 'time_format', '', 'g:i a', false ),
+		);
+	}
 }