Index: src/js/_enqueues/admin/common.js
===================================================================
--- src/js/_enqueues/admin/common.js	(revision 46248)
+++ src/js/_enqueues/admin/common.js	(working copy)
@@ -1274,6 +1274,8 @@
 		init: function() {
 			var self = this;
 
+			this.maybeDisableSortables = this.maybeDisableSortables.bind( this );
+
 			// Modify functionality based on custom activate/deactivate event
 			$document.on( 'wp-responsive-activate.wp-responsive', function() {
 				self.activate();
@@ -1313,16 +1315,34 @@
 			$document.on( 'wp-window-resized.wp-responsive', $.proxy( this.trigger, this ) );
 
 			// This needs to run later as UI Sortable may be initialized later on $(document).ready().
-			$window.on( 'load.wp-responsive', function() {
-				var width = navigator.userAgent.indexOf('AppleWebKit/') > -1 ? $window.width() : window.innerWidth;
+			$window.on( 'load.wp-responsive', this.maybeDisableSortables );
+			$document.on( 'postbox-toggled', this.maybeDisableSortables );
 
-				if ( width <= 782 ) {
-					self.disableSortables();
-				}
-			});
+			// When the screen columns are changed, potentially disable sortables.
+			$( '#screen-options-wrap input' ).on( 'click', this.maybeDisableSortables );
 		},
 
 		/**
+		 * Disable sortables if there is only one metabox, or the screen is in one column mode. Otherwise, enable sortables.
+		 *
+		 * @since 5.3.0
+		 *
+		 * @returns {void}
+		 */
+		maybeDisableSortables: function() {
+			var width = navigator.userAgent.indexOf('AppleWebKit/') > -1 ? $window.width() : window.innerWidth;
+
+			if (
+				( width <= 782 ) ||
+				( 1 >= $sortables.find( '.ui-sortable-handle:visible' ).length && jQuery( '.columns-prefs-1 input' ).prop( 'checked' ) )
+			) {
+				this.disableSortables();
+			} else {
+				this.enableSortables();
+			}
+		},
+
+		/**
 		 * Changes properties of body and admin menu.
 		 *
 		 * Pins and unpins the menu and adds the auto-fold class to the body.
@@ -1356,7 +1376,8 @@
 		deactivate: function() {
 			setPinMenu();
 			$adminmenu.removeData('wp-responsive');
-			this.enableSortables();
+
+			this.maybeDisableSortables();
 		},
 
 		/**
@@ -1391,6 +1412,8 @@
 			} else {
 				this.disableOverlay();
 			}
+
+			this.maybeDisableSortables();
 		},
 
 		/**
@@ -1439,6 +1462,7 @@
 			if ( $sortables.length ) {
 				try {
 					$sortables.sortable( 'disable' );
+					$sortables.find( '.ui-sortable-handle' ).addClass( 'is-non-sortable' );
 				} catch ( e ) {}
 			}
 		},
@@ -1454,6 +1478,7 @@
 			if ( $sortables.length ) {
 				try {
 					$sortables.sortable( 'enable' );
+					$sortables.find( '.ui-sortable-handle' ).removeClass( 'is-non-sortable' );
 				} catch ( e ) {}
 			}
 		}
Index: src/wp-admin/css/common.css
===================================================================
--- src/wp-admin/css/common.css	(revision 46248)
+++ src/wp-admin/css/common.css	(working copy)
@@ -2041,6 +2041,11 @@
 	cursor: move;
 }
 
+.js .widget .widget-top.is-non-sortable,
+.js .postbox .hndle.is-non-sortable {
+	cursor: auto;
+}
+
 .hndle a {
 	font-size: 11px;
 	font-weight: 400;