diff --git a/packages/react-native/src/private/webapis/mutationobserver/MutationObserver.js b/packages/react-native/src/private/webapis/mutationobserver/MutationObserver.js
index 1ee166b78cd..cb170f30837 100644
--- a/packages/react-native/src/private/webapis/mutationobserver/MutationObserver.js
+++ b/packages/react-native/src/private/webapis/mutationobserver/MutationObserver.js
@@ -121,13 +121,15 @@ export default class MutationObserver {
       MutationObserverManager.unobserve(mutationObserverId, target);
     }
 
-    MutationObserverManager.observe({
+    const didStartObserving = MutationObserverManager.observe({
       mutationObserverId,
       target,
       subtree: Boolean(options?.subtree),
     });
 
-    this._observationTargets.add(target);
+    if (didStartObserving) {
+      this._observationTargets.add(target);
+    }
   }
 
   _unobserve(target: ReactNativeElement): void {
diff --git a/packages/react-native/src/private/webapis/mutationobserver/MutationObserverManager.js b/packages/react-native/src/private/webapis/mutationobserver/MutationObserverManager.js
index 3d2c5d9eb7e..68367c30c28 100644
--- a/packages/react-native/src/private/webapis/mutationobserver/MutationObserverManager.js
+++ b/packages/react-native/src/private/webapis/mutationobserver/MutationObserverManager.js
@@ -43,6 +43,13 @@ const registeredMutationObservers: Map<
   $ReadOnly<{observer: MutationObserver, callback: MutationObserverCallback}>,
 > = new Map();
 
+// The mapping between ReactNativeElement and their corresponding shadow node
+// needs to be kept here because React removes the link when unmounting.
+const targetToShadowNodeMap: WeakMap<
+  ReactNativeElement,
+  ReturnType<typeof getShadowNode>,
+> = new WeakMap();
+
 /**
  * Registers the given mutation observer and returns a unique ID for it,
  * which is required to start observing targets.
@@ -85,10 +92,10 @@ export function observe({
   mutationObserverId: MutationObserverId,
   target: ReactNativeElement,
   subtree: boolean,
-}): void {
+}): boolean {
   if (NativeMutationObserver == null) {
     warnNoNativeMutationObserver();
-    return;
+    return false;
   }
 
   const registeredObserver =
@@ -97,17 +104,17 @@ export function observe({
     console.error(
       `MutationObserverManager: could not start observing target because MutationObserver with ID ${mutationObserverId} was not registered.`,
     );
-    return;
+    return false;
   }
 
   const targetShadowNode = getShadowNode(target);
   if (targetShadowNode == null) {
-    console.error(
-      'MutationObserverManager: could not find reference to host node from target',
-    );
-    return;
+    // The target is disconnected. We can't observe it anymore.
+    return false;
   }
 
+  targetToShadowNodeMap.set(target, targetShadowNode);
+
   if (!isConnected) {
     NativeMutationObserver.connect(
       notifyMutationObservers,
@@ -121,11 +128,13 @@ export function observe({
     isConnected = true;
   }
 
-  return NativeMutationObserver.observe({
+  NativeMutationObserver.observe({
     mutationObserverId,
     targetShadowNode,
     subtree,
   });
+
+  return true;
 }
 
 export function unobserve(
@@ -146,10 +155,10 @@ export function unobserve(
     return;
   }
 
-  const targetShadowNode = getShadowNode(target);
+  const targetShadowNode = targetToShadowNodeMap.get(target);
   if (targetShadowNode == null) {
     console.error(
-      'MutationObserverManager: could not find reference to host node from target',
+      'MutationObserverManager: could not find registration data for target',
     );
     return;
   }