diff --git a/src/material-experimental/mdc-autocomplete/autocomplete.spec.ts b/src/material-experimental/mdc-autocomplete/autocomplete.spec.ts
index 852e62aaf05c..2489b0001024 100644
--- a/src/material-experimental/mdc-autocomplete/autocomplete.spec.ts
+++ b/src/material-experimental/mdc-autocomplete/autocomplete.spec.ts
@@ -9,6 +9,7 @@ import {
   dispatchEvent,
   dispatchFakeEvent,
   dispatchKeyboardEvent,
+  dispatchMouseEvent,
   MockNgZone,
   typeInElement,
 } from '../../cdk/testing/private';
@@ -1395,6 +1396,24 @@ describe('MDC-based MatAutocomplete', () => {
         .toBeFalsy();
     }));
 
+    it('should not close when a click event occurs on the outside while the panel has focus',
+      fakeAsync(() => {
+        const trigger = fixture.componentInstance.trigger;
+
+        input.focus();
+        flush();
+        fixture.detectChanges();
+
+        expect(document.activeElement).toBe(input, 'Expected input to be focused.');
+        expect(trigger.panelOpen).toBe(true, 'Expected panel to be open.');
+
+        dispatchMouseEvent(document.body, 'click');
+        fixture.detectChanges();
+
+        expect(document.activeElement).toBe(input, 'Expected input to continue to be focused.');
+        expect(trigger.panelOpen).toBe(true, 'Expected panel to stay open.');
+      }));
+
     it('should reset the active option when closing with the escape key', fakeAsync(() => {
       const trigger = fixture.componentInstance.trigger;
 
diff --git a/src/material/autocomplete/autocomplete-trigger.ts b/src/material/autocomplete/autocomplete-trigger.ts
index fa6f0b15d39e..be87ee1de4f7 100644
--- a/src/material/autocomplete/autocomplete-trigger.ts
+++ b/src/material/autocomplete/autocomplete-trigger.ts
@@ -354,6 +354,11 @@ export abstract class _MatAutocompleteTriggerBase
         return (
           this._overlayAttached &&
           clickTarget !== this._element.nativeElement &&
+          // Normally focus moves inside `mousedown` so this condition will almost always be
+          // true. Its main purpose is to handle the case where the input is focused from an
+          // outside click which propagates up to the `body` listener within the same sequence
+          // and causes the panel to close immediately (see #3106).
+          this._document.activeElement !== this._element.nativeElement &&
           (!formField || !formField.contains(clickTarget)) &&
           (!customOrigin || !customOrigin.contains(clickTarget)) &&
           !!this._overlayRef &&
diff --git a/src/material/autocomplete/autocomplete.spec.ts b/src/material/autocomplete/autocomplete.spec.ts
index b905b193b4a3..136aa58aae05 100644
--- a/src/material/autocomplete/autocomplete.spec.ts
+++ b/src/material/autocomplete/autocomplete.spec.ts
@@ -11,7 +11,8 @@ import {
   dispatchFakeEvent,
   dispatchKeyboardEvent,
   typeInElement,
-} from '../../cdk/testing/private';
+  dispatchMouseEvent,
+} from '@angular/cdk/testing/private';
 import {
   ChangeDetectionStrategy,
   Component,
@@ -1378,6 +1379,24 @@ describe('MatAutocomplete', () => {
         .toBeFalsy();
     }));
 
+    it('should not close when a click event occurs on the outside while the panel has focus',
+      fakeAsync(() => {
+        const trigger = fixture.componentInstance.trigger;
+
+        input.focus();
+        flush();
+        fixture.detectChanges();
+
+        expect(document.activeElement).toBe(input, 'Expected input to be focused.');
+        expect(trigger.panelOpen).toBe(true, 'Expected panel to be open.');
+
+        dispatchMouseEvent(document.body, 'click');
+        fixture.detectChanges();
+
+        expect(document.activeElement).toBe(input, 'Expected input to continue to be focused.');
+        expect(trigger.panelOpen).toBe(true, 'Expected panel to stay open.');
+      }));
+
     it('should reset the active option when closing with the escape key', fakeAsync(() => {
       const trigger = fixture.componentInstance.trigger;