diff --git a/packages/components/CHANGELOG.md b/packages/components/CHANGELOG.md
index 248802890e46d6..beee58ba8dd240 100644
--- a/packages/components/CHANGELOG.md
+++ b/packages/components/CHANGELOG.md
@@ -17,6 +17,7 @@
 -   `Popover`: make sure offset middleware always applies the latest frame offset values ([#43329](https://github.com/WordPress/gutenberg/pull/43329/)).
 -   `Dropdown`: anchor popover to the dropdown wrapper (instead of the toggle) ([#43377](https://github.com/WordPress/gutenberg/pull/43377/)).
 -   `Guide`: Fix error when rendering with no pages ([#43380](https://github.com/WordPress/gutenberg/pull/43380/)).
+-   `Popover`: Ensure position is correct when a nested popover's parent references an element in an iframe and the iframe is scrolled ([#43544](https://github.com/WordPress/gutenberg/pull/43544/)).
 
 ### Enhancements
 
diff --git a/packages/components/src/popover/index.js b/packages/components/src/popover/index.js
index c40804e1164e23..3b90de04928f40 100644
--- a/packages/components/src/popover/index.js
+++ b/packages/components/src/popover/index.js
@@ -48,6 +48,10 @@ import {
 	positionToPlacement,
 	placementToMotionAnimationProps,
 } from './utils';
+import {
+	useRootReferenceDocument,
+	RootReferenceDocumentProvider,
+} from './root-reference-document-context';
 
 /**
  * Name of slot in which popover should fill.
@@ -430,74 +434,108 @@ const Popover = (
 		};
 	}, [ referenceOwnerDocument, update ] );
 
+	// If the root document is scrolled trigger an update of the popover
+	// position. This covers cases where a popover is a child of another
+	// popover, and the first popover in the chain references an element
+	// in an iframe.
+	const rootReferenceDocument = useRootReferenceDocument();
+	useLayoutEffect( () => {
+		// Return early if the root document is the same as the owner document,
+		// as the scroll event will be listened to in other code.
+		const isSameDocument = rootReferenceDocument === referenceOwnerDocument;
+
+		// Return early if this isn't an iframe document.
+		const isNotIframeDocument = rootReferenceDocument === document;
+
+		if (
+			! rootReferenceDocument ||
+			isSameDocument ||
+			isNotIframeDocument
+		) {
+			return;
+		}
+
+		rootReferenceDocument.addEventListener( 'scroll', update );
+		return () =>
+			rootReferenceDocument?.removeEventListener( 'scroll', update );
+	}, [ referenceOwnerDocument, rootReferenceDocument, update ] );
+
 	const mergedFloatingRef = useMergeRefs( [
 		floating,
 		dialogRef,
 		forwardedRef,
 	] );
 
-	// Disable reason: We care to capture the _bubbled_ events from inputs
-	// within popover as inferring close intent.
-
 	let content = (
-		// eslint-disable-next-line jsx-a11y/no-noninteractive-element-interactions
-		// eslint-disable-next-line jsx-a11y/no-static-element-interactions
-		<MaybeAnimatedWrapper
-			shouldAnimate={ animate && ! isExpanded }
-			placement={ computedPlacement }
-			className={ classnames( 'components-popover', className, {
-				'is-expanded': isExpanded,
-				'is-alternate': isAlternate,
-			} ) }
-			{ ...contentProps }
-			ref={ mergedFloatingRef }
-			{ ...dialogProps }
-			tabIndex="-1"
-			style={
-				isExpanded
-					? undefined
-					: {
-							position: strategy,
-							left: Number.isNaN( x ) ? 0 : x,
-							top: Number.isNaN( y ) ? 0 : y,
-					  }
-			}
+		<RootReferenceDocumentProvider
+			// Don't overwrite the root document if it's already set.
+			// This ensures only the reference document from the very
+			// root popover is provided.
+			value={ rootReferenceDocument ?? referenceOwnerDocument }
 		>
-			{ /* Prevents scroll on the document */ }
-			{ isExpanded && <ScrollLock /> }
-			{ isExpanded && (
-				<div className="components-popover__header">
-					<span className="components-popover__header-title">
-						{ headerTitle }
-					</span>
-					<Button
-						className="components-popover__close"
-						icon={ close }
-						onClick={ onClose }
-					/>
-				</div>
-			) }
-			<div className="components-popover__content">{ children }</div>
-			{ hasArrow && (
-				<div
-					ref={ arrowRef }
-					className={ [
-						'components-popover__arrow',
-						`is-${ computedPlacement.split( '-' )[ 0 ] }`,
-					].join( ' ' ) }
-					style={ {
-						left: Number.isFinite( arrowData?.x )
-							? `${ arrowData.x }px`
-							: '',
-						top: Number.isFinite( arrowData?.y )
-							? `${ arrowData.y }px`
-							: '',
-					} }
-				>
-					<ArrowTriangle />
-				</div>
-			) }
-		</MaybeAnimatedWrapper>
+			{
+				// Disable reason: We care to capture the _bubbled_ events from inputs
+				// within popover as inferring close intent.
+				// eslint-disable-next-line jsx-a11y/no-noninteractive-element-interactions
+				// eslint-disable-next-line jsx-a11y/no-static-element-interactions
+			 }
+			<MaybeAnimatedWrapper
+				shouldAnimate={ animate && ! isExpanded }
+				placement={ computedPlacement }
+				className={ classnames( 'components-popover', className, {
+					'is-expanded': isExpanded,
+					'is-alternate': isAlternate,
+				} ) }
+				{ ...contentProps }
+				ref={ mergedFloatingRef }
+				{ ...dialogProps }
+				tabIndex="-1"
+				style={
+					isExpanded
+						? undefined
+						: {
+								position: strategy,
+								left: Number.isNaN( x ) ? 0 : x,
+								top: Number.isNaN( y ) ? 0 : y,
+						  }
+				}
+			>
+				{ /* Prevents scroll on the document */ }
+				{ isExpanded && <ScrollLock /> }
+				{ isExpanded && (
+					<div className="components-popover__header">
+						<span className="components-popover__header-title">
+							{ headerTitle }
+						</span>
+						<Button
+							className="components-popover__close"
+							icon={ close }
+							onClick={ onClose }
+						/>
+					</div>
+				) }
+				<div className="components-popover__content">{ children }</div>
+				{ hasArrow && (
+					<div
+						ref={ arrowRef }
+						className={ [
+							'components-popover__arrow',
+							`is-${ computedPlacement.split( '-' )[ 0 ] }`,
+						].join( ' ' ) }
+						style={ {
+							left: Number.isFinite( arrowData?.x )
+								? `${ arrowData.x }px`
+								: '',
+							top: Number.isFinite( arrowData?.y )
+								? `${ arrowData.y }px`
+								: '',
+						} }
+					>
+						<ArrowTriangle />
+					</div>
+				) }
+			</MaybeAnimatedWrapper>
+		</RootReferenceDocumentProvider>
 	);
 
 	if ( slot.ref ) {
diff --git a/packages/components/src/popover/root-reference-document-context.js b/packages/components/src/popover/root-reference-document-context.js
new file mode 100644
index 00000000000000..855954a83f667f
--- /dev/null
+++ b/packages/components/src/popover/root-reference-document-context.js
@@ -0,0 +1,10 @@
+/**
+ * WordPress dependencies
+ */
+import { createContext, useContext } from '@wordpress/element';
+
+const RootReferenceDocumentContext = createContext( undefined );
+export const useRootReferenceDocument = () =>
+	useContext( RootReferenceDocumentContext );
+export const RootReferenceDocumentProvider =
+	RootReferenceDocumentContext.Provider;