Index: wp-admin/includes/upgrade.php
--- wp-admin/includes/upgrade.php
+++ wp-admin/includes/upgrade.php
@@ -1208,7 +1208,7 @@
 		add_site_option( 'siteurl', '' );
 
 	// 3.0 screen options key name changes.
-	if ( is_main_site() && !defined('DO_NOT_UPGRADE_GLOBAL_TABLES') ) {
+	if ( wp_can_upgrade_global_tables() ) {
 		$sql = "DELETE FROM $wpdb->usermeta
 			WHERE meta_key LIKE %s
 			OR meta_key LIKE %s
@@ -1243,7 +1243,7 @@
 function upgrade_330() {
 	global $wp_current_db_version, $wpdb, $wp_registered_widgets, $sidebars_widgets;
 
-	if ( $wp_current_db_version < 19061 && is_main_site() && ! defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) ) {
+	if ( $wp_current_db_version < 19061 && wp_can_upgrade_global_tables() ) {
 		$wpdb->query( "DELETE FROM $wpdb->usermeta WHERE meta_key IN ('show_admin_bar_admin', 'plugins_last_view')" );
 	}
 
@@ -1324,7 +1324,7 @@
 		$wpdb->show_errors();
 	}
 
-	if ( $wp_current_db_version < 20022 && is_main_site() && ! defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) ) {
+	if ( $wp_current_db_version < 20022 && wp_can_upgrade_global_tables() ) {
 		$wpdb->query( "DELETE FROM $wpdb->usermeta WHERE meta_key = 'themes_last_view'" );
 	}
 
@@ -1348,7 +1348,7 @@
 	if ( $wp_current_db_version < 22006 && $wpdb->get_var( "SELECT link_id FROM $wpdb->links LIMIT 1" ) )
 		update_option( 'link_manager_enabled', 1 ); // Previously set to 0 by populate_options()
 
-	if ( $wp_current_db_version < 21811 && is_main_site() && ! defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) ) {
+	if ( $wp_current_db_version < 21811 && wp_can_upgrade_global_tables() ) {
 		$meta_keys = array();
 		foreach ( array_merge( get_post_types(), get_taxonomies() ) as $name ) {
 			if ( false !== strpos( $name, '-' ) )
@@ -1564,11 +1564,11 @@
 
 	// 4.2
 	if ( $wp_current_db_version < 31351 && $wpdb->charset === 'utf8mb4' ) {
-		if ( ! ( defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) && DO_NOT_UPGRADE_GLOBAL_TABLES ) ) {
-			$wpdb->query( "ALTER TABLE $wpdb->usermeta DROP INDEX meta_key, ADD INDEX meta_key(meta_key(191))" );
-			$wpdb->query( "ALTER TABLE $wpdb->site DROP INDEX domain, ADD INDEX domain(domain(140),path(51))" );
-			$wpdb->query( "ALTER TABLE $wpdb->sitemeta DROP INDEX meta_key, ADD INDEX meta_key(meta_key(191))" );
-			$wpdb->query( "ALTER TABLE $wpdb->signups DROP INDEX domain, ADD INDEX domain(domain(140),path(51))" );
+		if ( wp_can_upgrade_global_tables() ) {
+			$wpdb->query( "ALTER TABLE `{$wpdb->usermeta}` DROP INDEX meta_key, ADD INDEX meta_key(meta_key(191))" );
+			$wpdb->query( "ALTER TABLE `{$wpdb->site}` DROP INDEX domain, ADD INDEX domain(domain(140),path(51))" );
+			$wpdb->query( "ALTER TABLE `{$wpdb->sitemeta}` DROP INDEX meta_key, ADD INDEX meta_key(meta_key(191))" );
+			$wpdb->query( "ALTER TABLE `{$wpdb->signups}` DROP INDEX domain, ADD INDEX domain(domain(140),path(51))" );
 
 			$tables = $wpdb->tables( 'global' );
 
@@ -1870,8 +1870,8 @@
 
 	$global_tables = $wpdb->tables( 'global' );
 	foreach ( $cqueries as $table => $qry ) {
-		// Upgrade global tables only for the main site. Don't upgrade at all if DO_NOT_UPGRADE_GLOBAL_TABLES is defined.
-		if ( in_array( $table, $global_tables ) && ( !is_main_site() || defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) ) ) {
+		// Upgrade global tables only for the main site. Don't upgrade at all if conditions are not optimal.
+		if ( in_array( $table, $global_tables ) && ! wp_can_upgrade_global_tables() ) {
 			unset( $cqueries[ $table ], $for_update[ $table ] );
 			continue;
 		}
@@ -2380,7 +2380,7 @@
 	}
 
 	// Multisite schema upgrades.
-	if ( $wp_current_db_version < 25448 && is_multisite() && ! defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) && is_main_network() ) {
+	if ( $wp_current_db_version < 25448 && wp_can_upgrade_global_tables() ) {
 
 		// Upgrade verions prior to 3.7
 		if ( $wp_current_db_version < 25179 ) {
@@ -2403,7 +2403,7 @@
 
 	// Upgrade versions prior to 4.2.
 	if ( $wp_current_db_version < 31351 ) {
-		if ( ! is_multisite() ) {
+		if ( upgrade_global_tables() ) {
 			$wpdb->query( "ALTER TABLE $wpdb->usermeta DROP INDEX meta_key, ADD INDEX meta_key(meta_key(191))" );
 		}
 		$wpdb->query( "ALTER TABLE $wpdb->terms DROP INDEX slug, ADD INDEX slug(slug(191))" );
@@ -2438,3 +2438,44 @@
 	dbDelta( $ms_queries );
 }
 endif;
+
+/**
+ * Can global tables be upgraded?
+ * 
+ * This function performs a series of checks to ensure the environment allows
+ * for the safe upgrading of global WordPress database tables. It is necessary
+ * because global tables will commonly grow to millions of rows on large
+ * installations, and the ability to control their upgrade routines can be
+ * critical to the operation of large networks.
+ *
+ * In a future iteration, this function may use `wp_is_large_network()` to more-
+ * intelligently prevent global table upgrades. Until then, we make sure
+ * WordPress is on the main site of the main network, to avoid running queries
+ * more than once in multi-site or multi-network environments.
+ *
+ * @since WordPress 4.3.0
+ *
+ * @return boolean
+ */
+function wp_can_upgrade_global_tables() {
+
+	// Assume global tables should be updated
+	$retval = true;
+
+	// Return false early if explicitly not upgrading
+	if ( defined( 'DO_NOT_UPGRADE_GLOBAL_TABLES' ) ) {
+		return false;
+	}
+
+	// Set to false if not on main network (does not matter if not multi-network)
+	if ( ! is_main_network() ) {
+		$retval = false;
+	}
+
+	// Set to false if not on main site of current network (does not matter if not multi-site)
+	if ( ! is_main_site() ) {
+		$retval = false;
+	}
+
+	return (bool) apply_filters( 'wp_can_upgrade_global_tables', $retval );
+}