diff --git a/src/wp-admin/includes/schema.php b/src/wp-admin/includes/schema.php
index 92fd6d6619b7..1d1cbcbc2fa6 100644
--- a/src/wp-admin/includes/schema.php
+++ b/src/wp-admin/includes/schema.php
@@ -1159,6 +1159,12 @@ function populate_network_meta( $network_id, array $meta = array() ) {
 		}
 	}
 
+	if ( function_exists( 'clean_network_cache' ) ) {
+		clean_network_cache( $network_id );
+	} else {
+		wp_cache_delete( $network_id, 'networks' );
+	}
+
 	wp_cache_delete( 'networks_have_paths', 'site-options' );
 
 	if ( ! is_multisite() ) {
diff --git a/src/wp-includes/class-wp-network.php b/src/wp-includes/class-wp-network.php
index 4926c0d8b548..849dfc127134 100644
--- a/src/wp-includes/class-wp-network.php
+++ b/src/wp-includes/class-wp-network.php
@@ -101,16 +101,20 @@ public static function get_instance( $network_id ) {
 
 		$_network = wp_cache_get( $network_id, 'networks' );
 
-		if ( ! $_network ) {
+		if ( false === $_network ) {
 			$_network = $wpdb->get_row( $wpdb->prepare( "SELECT * FROM {$wpdb->site} WHERE id = %d LIMIT 1", $network_id ) );
 
 			if ( empty( $_network ) || is_wp_error( $_network ) ) {
-				return false;
+				$_network = -1;
 			}
 
 			wp_cache_add( $network_id, $_network, 'networks' );
 		}
 
+		if ( is_numeric( $_network ) ) {
+			return false;
+		}
+
 		return new WP_Network( $_network );
 	}
 
@@ -231,8 +235,8 @@ private function get_main_site_id() {
 			return (int) $this->blog_id;
 		}
 
-		if ( ( defined( 'DOMAIN_CURRENT_SITE' ) && defined( 'PATH_CURRENT_SITE' ) && $this->domain === DOMAIN_CURRENT_SITE && $this->path === PATH_CURRENT_SITE )
-			|| ( defined( 'SITE_ID_CURRENT_SITE' ) && $this->id == SITE_ID_CURRENT_SITE ) ) {
+		if ( ( defined( 'DOMAIN_CURRENT_SITE' ) && defined( 'PATH_CURRENT_SITE' ) && DOMAIN_CURRENT_SITE === $this->domain && PATH_CURRENT_SITE === $this->path )
+			|| ( defined( 'SITE_ID_CURRENT_SITE' ) && SITE_ID_CURRENT_SITE == $this->id ) ) {
 			if ( defined( 'BLOG_ID_CURRENT_SITE' ) ) {
 				$this->blog_id = (string) BLOG_ID_CURRENT_SITE;
 
@@ -457,7 +461,7 @@ public static function get_by_path( $domain = '', $path = '', $segments = null )
 					break;
 				}
 			}
-			if ( $network->path === '/' ) {
+			if ( '/' === $network->path ) {
 				$found = true;
 				break;
 			}
diff --git a/src/wp-includes/class-wp-site.php b/src/wp-includes/class-wp-site.php
index b0459be2d4e1..e1839fed9e4c 100644
--- a/src/wp-includes/class-wp-site.php
+++ b/src/wp-includes/class-wp-site.php
@@ -162,16 +162,20 @@ public static function get_instance( $site_id ) {
 
 		$_site = wp_cache_get( $site_id, 'sites' );
 
-		if ( ! $_site ) {
+		if ( false === $_site ) {
 			$_site = $wpdb->get_row( $wpdb->prepare( "SELECT * FROM {$wpdb->blogs} WHERE blog_id = %d LIMIT 1", $site_id ) );
 
 			if ( empty( $_site ) || is_wp_error( $_site ) ) {
-				return false;
+				$_site = -1;
 			}
 
 			wp_cache_add( $site_id, $_site, 'sites' );
 		}
 
+		if ( is_numeric( $_site ) ) {
+			return false;
+		}
+
 		return new WP_Site( $_site );
 	}
 
diff --git a/src/wp-includes/ms-site.php b/src/wp-includes/ms-site.php
index 952697351063..039eb488d992 100644
--- a/src/wp-includes/ms-site.php
+++ b/src/wp-includes/ms-site.php
@@ -69,14 +69,14 @@ function wp_insert_site( array $data ) {
 		return new WP_Error( 'db_insert_error', __( 'Could not insert site into the database.' ), $wpdb->last_error );
 	}
 
+	clean_blog_cache( $wpdb->insert_id );
+
 	$new_site = get_site( $wpdb->insert_id );
 
 	if ( ! $new_site ) {
 		return new WP_Error( 'get_site_error', __( 'Could not retrieve site data.' ) );
 	}
 
-	clean_blog_cache( $new_site );
-
 	/**
 	 * Fires once a site has been inserted into the database.
 	 *
diff --git a/tests/phpunit/tests/multisite/network.php b/tests/phpunit/tests/multisite/network.php
index 18e8510e5b86..0a5d57cb9903 100644
--- a/tests/phpunit/tests/multisite/network.php
+++ b/tests/phpunit/tests/multisite/network.php
@@ -613,6 +613,49 @@ public function test_network_blog_id_set() {
 
 			$this->assertSame( (string) self::$different_site_ids[0], $network->blog_id );
 		}
+
+		/**
+		 * @ticket 42251
+		 */
+		public function test_get_network_not_found_cache() {
+			global $wpdb;
+
+			$new_network_id = $this->_get_next_network_id();
+			$this->assertNull( get_network( $new_network_id ) );
+
+			$num_queries = $wpdb->num_queries;
+			$this->assertNull( get_network( $new_network_id ) );
+			$this->assertSame( $num_queries, $wpdb->num_queries );
+		}
+
+		/**
+		 * @ticket 42251
+		 */
+		public function test_get_network_not_found_cache_clear() {
+			$new_network_id = $this->_get_next_network_id();
+			$this->assertNull( get_network( $new_network_id ) );
+
+			$new_network = $this->factory()->network->create_and_get();
+
+			// Double-check we got the ID of the new network correct.
+			$this->assertEquals( $new_network_id, $new_network->id );
+
+			// Verify that if we fetch the network now, it's no longer false.
+			$fetched_network = get_network( $new_network_id );
+			$this->assertInstanceOf( 'WP_Network', $fetched_network );
+			$this->assertEquals( $new_network_id, $fetched_network->id );
+		}
+
+		/**
+		 * Gets the ID of the site with the highest ID
+		 * @return int
+		 */
+		protected function _get_next_network_id() {
+			global $wpdb;
+			//create an extra network, just to make sure we know the ID of the following one
+			static::factory()->network->create();
+			return (int) $wpdb->get_var( 'SELECT id FROM ' . $wpdb->site . ' ORDER BY id DESC LIMIT 1' ) + 1;
+		}
 	}
 
 endif;
diff --git a/tests/phpunit/tests/multisite/site.php b/tests/phpunit/tests/multisite/site.php
index 2beb4ca090a2..f0aa28a06d1c 100644
--- a/tests/phpunit/tests/multisite/site.php
+++ b/tests/phpunit/tests/multisite/site.php
@@ -2383,6 +2383,51 @@ public function test_wpmu_new_blog_action_backward_compatible( $meta, $expected_
 			$this->wp_initialize_site_meta = array();
 		}
 
+		/**
+		 * @ticket 42251
+		 */
+		public function test_get_site_not_found_cache() {
+			global $wpdb;
+
+			$new_site_id = $this->_get_next_site_id();
+			$this->assertNull( get_site( $new_site_id ) );
+
+			$num_queries = $wpdb->num_queries;
+			$this->assertNull( get_site( $new_site_id ) );
+			$this->assertSame( $num_queries, $wpdb->num_queries );
+		}
+
+		/**
+		 * @ticket 42251
+		 */
+		public function test_get_site_not_found_cache_clear() {
+			$new_site_id = $this->_get_next_site_id();
+			$this->assertNull( get_site( $new_site_id ) );
+
+			$new_site = $this->factory()->blog->create_and_get();
+
+			// Double-check we got the ID of the new site correct.
+			$this->assertEquals( $new_site_id, $new_site->blog_id );
+
+			// Verify that if we fetch the site now, it's no longer false.
+			$fetched_site = get_site( $new_site_id );
+			$this->assertInstanceOf( 'WP_Site', $fetched_site );
+			$this->assertEquals( $new_site_id, $fetched_site->blog_id );
+
+		}
+
+		/**
+		 * Gets the ID of the next site that will get inserted
+		 * @return int
+		 */
+		protected function _get_next_site_id() {
+			global $wpdb;
+			//create an entry
+			static::factory()->blog->create();
+			//get the ID after it
+			return (int) $wpdb->get_var( 'SELECT blog_id FROM ' . $wpdb->blogs . ' ORDER BY blog_ID DESC LIMIT 1' ) + 1;
+		}
+
 		/**
 		 * Capture the $meta value passed to the wpmu_new_blog action and compare it.
 		 */