diff --git a/UNRELEASED.md b/UNRELEASED.md
index 30d0005828b..99bf61b4aa6 100644
--- a/UNRELEASED.md
+++ b/UNRELEASED.md
@@ -10,6 +10,7 @@
 - Fixed `DropZone` not supporting new file selection when `allowMultiple` is `false` ([#2737](https://github.com/Shopify/polaris-react/pull/2737)) ([#2737](https://github.com/Shopify/polaris-react/pull/2737))
 - Fixed `DropZone` not supporting new file selection when `allowMultiple` is `false` ([#2737](https://github.com/Shopify/polaris-react/pull/2737))
 - Fixed `Pagination` sizing on small screens with tooltips ([2747](https://github.com/Shopify/polaris-react/pull/2747))
+- Fixed `Popover` setting a `tabindex` and other accessibility attributes on the activator wrapper when the `activator` is disabled ([#2473](https://github.com/Shopify/polaris-react/pull/2473))
 
 ### Documentation
 
diff --git a/src/components/Popover/Popover.tsx b/src/components/Popover/Popover.tsx
index 33c0a587e55..f1c5bd130f3 100644
--- a/src/components/Popover/Popover.tsx
+++ b/src/components/Popover/Popover.tsx
@@ -5,8 +5,10 @@ import React, {
   useState,
   AriaAttributes,
 } from 'react';
-import {findFirstFocusableNode} from '@shopify/javascript-utilities/focus';
-import {focusNextFocusableNode} from '../../utilities/focus';
+import {
+  findFirstFocusableNode,
+  focusNextFocusableNode,
+} from '../../utilities/focus';
 import {Portal} from '../Portal';
 import {portal} from '../shared';
 import {useUniqueId} from '../../utilities/unique-id';
@@ -90,9 +92,20 @@ export const Popover: React.FunctionComponent<PopoverProps> & {
     }
 
     const firstFocusable = findFirstFocusableNode(activatorContainer.current);
-    const focusableActivator = firstFocusable || activatorContainer.current;
-    setActivatorAttributes(focusableActivator, {id, active, ariaHaspopup});
-  }, [active, ariaHaspopup, id]);
+    const focusableActivator: HTMLElement & {
+      disabled?: boolean;
+    } = firstFocusable || activatorContainer.current;
+
+    const activatorDisabled =
+      'disabled' in focusableActivator && Boolean(focusableActivator.disabled);
+
+    setActivatorAttributes(focusableActivator, {
+      id,
+      active,
+      ariaHaspopup,
+      activatorDisabled,
+    });
+  }, [id, active, ariaHaspopup]);
 
   const handleClose = (source: PopoverCloseSource) => {
     onClose(source);
diff --git a/src/components/Popover/set-activator-attributes.ts b/src/components/Popover/set-activator-attributes.ts
index 66af0cd288b..519cbe949ef 100644
--- a/src/components/Popover/set-activator-attributes.ts
+++ b/src/components/Popover/set-activator-attributes.ts
@@ -4,15 +4,20 @@ export function setActivatorAttributes(
   activator: HTMLElement,
   {
     id,
-    active,
+    active = false,
     ariaHaspopup,
+    activatorDisabled = false,
   }: {
     id: string;
     active: boolean;
     ariaHaspopup: AriaAttributes['aria-haspopup'];
+    activatorDisabled: boolean;
   },
 ) {
-  activator.tabIndex = activator.tabIndex || 0;
+  if (!activatorDisabled) {
+    activator.tabIndex = activator.tabIndex || 0;
+  }
+
   activator.setAttribute('aria-controls', id);
   activator.setAttribute('aria-owns', id);
   activator.setAttribute('aria-expanded', String(active));
diff --git a/src/components/Popover/tests/Popover.test.tsx b/src/components/Popover/tests/Popover.test.tsx
index 8ea0d0e146e..8572e4886bf 100644
--- a/src/components/Popover/tests/Popover.test.tsx
+++ b/src/components/Popover/tests/Popover.test.tsx
@@ -21,14 +21,39 @@ describe('<Popover />', () => {
     setActivatorAttributesSpy.mockRestore();
   });
 
-  it('invokes setActivatorAttributes with active, ariaHasPopup and id', () => {
+  it('invokes setActivatorAttributes with active, ariaHasPopup, activatorDisabled, and id', () => {
     mountWithApp(
       <Popover active={false} activator={<div>Activator</div>} onClose={spy} />,
     );
 
     expect(setActivatorAttributesSpy).toHaveBeenLastCalledWith(
       expect.any(Object),
-      {active: false, ariaHaspopup: undefined, id: 'Polarispopover1'},
+      {
+        active: false,
+        ariaHaspopup: undefined,
+        id: 'Polarispopover1',
+        activatorDisabled: false,
+      },
+    );
+  });
+
+  it('invokes setActivatorAttributes activatorDisabled true when the activator is disabled', () => {
+    mountWithApp(
+      <Popover
+        active={false}
+        activator={<button disabled>Activator</button>}
+        onClose={spy}
+      />,
+    );
+
+    expect(setActivatorAttributesSpy).toHaveBeenLastCalledWith(
+      expect.any(Object),
+      {
+        active: false,
+        ariaHaspopup: undefined,
+        id: 'Polarispopover1',
+        activatorDisabled: true,
+      },
     );
   });
 
diff --git a/src/components/Popover/tests/set-activator-attributes.test.ts b/src/components/Popover/tests/set-activator-attributes.test.ts
index 47f1a9fe042..515aa9e5894 100644
--- a/src/components/Popover/tests/set-activator-attributes.test.ts
+++ b/src/components/Popover/tests/set-activator-attributes.test.ts
@@ -4,31 +4,85 @@ describe('setActivatorAttributes', () => {
   const id = 'id';
   it('applies aria-controls to the activator', () => {
     const div = document.createElement('div');
-    setActivatorAttributes(div, {active: true, id, ariaHaspopup: true});
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: true,
+      activatorDisabled: false,
+    });
+
     expect(div.getAttribute('aria-controls')).toBe(id);
   });
 
   it('applies aria-owns to the activator', () => {
     const div = document.createElement('div');
-    setActivatorAttributes(div, {active: true, id, ariaHaspopup: true});
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: true,
+      activatorDisabled: false,
+    });
+
     expect(div.getAttribute('aria-owns')).toBe(id);
   });
 
   it('applies aria-expanded to the activator', () => {
     const div = document.createElement('div');
-    setActivatorAttributes(div, {active: true, id, ariaHaspopup: true});
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: true,
+      activatorDisabled: false,
+    });
+
     expect(div.getAttribute('aria-expanded')).toBe('true');
   });
 
   it('applies aria-haspopup to the activator', () => {
     const div = document.createElement('div');
-    setActivatorAttributes(div, {active: true, id, ariaHaspopup: true});
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: true,
+      activatorDisabled: false,
+    });
+
     expect(div.getAttribute('aria-haspopup')).toBe('true');
   });
 
   it("does not apply aria-haspopover when it's undefined", () => {
     const div = document.createElement('div');
-    setActivatorAttributes(div, {active: true, id, ariaHaspopup: undefined});
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: undefined,
+      activatorDisabled: false,
+    });
+
     expect(div.getAttribute('aria-haspopup')).toBeNull();
   });
+
+  it('applies tabindex to the activator', () => {
+    const div = document.createElement('div');
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: true,
+      activatorDisabled: false,
+    });
+
+    expect(div.getAttribute('tabindex')).toBe('-1');
+  });
+
+  it('does not apply tabindex when activatorDisabled is true', () => {
+    const div = document.createElement('div');
+    setActivatorAttributes(div, {
+      active: true,
+      id,
+      ariaHaspopup: undefined,
+      activatorDisabled: true,
+    });
+
+    expect(div.getAttribute('tabindex')).toBeNull();
+  });
 });
diff --git a/src/utilities/focus.ts b/src/utilities/focus.ts
index f01e446425d..3c482df31e8 100644
--- a/src/utilities/focus.ts
+++ b/src/utilities/focus.ts
@@ -34,6 +34,20 @@ export function nextFocusableNode(
   return null;
 }
 
+// Popover needs to be able to find its activator even if it is disabled, which FOCUSABLE_SELECTOR doesn't support.
+
+export function findFirstFocusableNode(
+  element: HTMLElement,
+): HTMLElement | null {
+  const focusableSelector = `a,button,frame,iframe,input:not([type=hidden]),select,textarea,*[tabindex]`;
+
+  if (matches(element, focusableSelector)) {
+    return element;
+  }
+
+  return element.querySelector(focusableSelector);
+}
+
 export function focusNextFocusableNode(node: HTMLElement, filter?: Filter) {
   const nextFocusable = nextFocusableNode(node, filter);
   if (nextFocusable && nextFocusable instanceof HTMLElement) {