diff --git a/packages/react-devtools-extensions/src/contentScripts/backendManager.js b/packages/react-devtools-extensions/src/contentScripts/backendManager.js
index 9d3ec414330ed..63519b506dd96 100644
--- a/packages/react-devtools-extensions/src/contentScripts/backendManager.js
+++ b/packages/react-devtools-extensions/src/contentScripts/backendManager.js
@@ -16,6 +16,7 @@ import {COMPACT_VERSION_NAME} from 'react-devtools-extensions/src/utils';
 import {getIsReloadAndProfileSupported} from 'react-devtools-shared/src/utils';
 
 let welcomeHasInitialized = false;
+const requiredBackends = new Set<string>();
 
 function welcome(event: $FlowFixMe) {
   if (
@@ -49,8 +50,6 @@ function welcome(event: $FlowFixMe) {
   setup(window.__REACT_DEVTOOLS_GLOBAL_HOOK__);
 }
 
-window.addEventListener('message', welcome);
-
 function setup(hook: ?DevToolsHook) {
   // this should not happen, but Chrome can be weird sometimes
   if (hook == null) {
@@ -71,20 +70,27 @@ function setup(hook: ?DevToolsHook) {
   updateRequiredBackends();
 
   // register renderers that inject themselves later.
-  hook.sub('renderer', ({renderer}) => {
+  const unsubscribeRendererListener = hook.sub('renderer', ({renderer}) => {
     registerRenderer(renderer, hook);
     updateRequiredBackends();
   });
 
   // listen for backend installations.
-  hook.sub('devtools-backend-installed', version => {
-    activateBackend(version, hook);
-    updateRequiredBackends();
+  const unsubscribeBackendInstallationListener = hook.sub(
+    'devtools-backend-installed',
+    version => {
+      activateBackend(version, hook);
+      updateRequiredBackends();
+    },
+  );
+
+  const unsubscribeShutdownListener: () => void = hook.sub('shutdown', () => {
+    unsubscribeRendererListener();
+    unsubscribeBackendInstallationListener();
+    unsubscribeShutdownListener();
   });
 }
 
-const requiredBackends = new Set<string>();
-
 function registerRenderer(renderer: ReactRenderer, hook: DevToolsHook) {
   let version = renderer.reconcilerVersion || renderer.version;
   if (!hasAssignedBackend(version)) {
@@ -139,6 +145,7 @@ function activateBackend(version: string, hook: DevToolsHook) {
     // If we received 'shutdown' from `agent`, we assume the `bridge` is already shutting down,
     // and that caused the 'shutdown' event on the `agent`, so we don't need to call `bridge.shutdown()` here.
     hook.emit('shutdown');
+    delete window.__REACT_DEVTOOLS_BACKEND_MANAGER_INJECTED__;
   });
 
   initBackend(hook, agent, window, getIsReloadAndProfileSupported());
@@ -178,3 +185,13 @@ function updateRequiredBackends() {
     '*',
   );
 }
+
+/*
+ * Make sure this is executed only once in case Frontend is reloaded multiple times while Backend is initializing
+ * We can't use `reactDevToolsAgent` field on a global Hook object, because it only cleaned up after both Frontend and Backend initialized
+ */
+if (!window.__REACT_DEVTOOLS_BACKEND_MANAGER_INJECTED__) {
+  window.__REACT_DEVTOOLS_BACKEND_MANAGER_INJECTED__ = true;
+
+  window.addEventListener('message', welcome);
+}
diff --git a/packages/react-devtools-shared/src/backend/agent.js b/packages/react-devtools-shared/src/backend/agent.js
index 88450fe29ebc9..3480c065bd8a9 100644
--- a/packages/react-devtools-shared/src/backend/agent.js
+++ b/packages/react-devtools-shared/src/backend/agent.js
@@ -754,6 +754,9 @@ export default class Agent extends EventEmitter<{
   shutdown: () => void = () => {
     // Clean up the overlay if visible, and associated events.
     this.emit('shutdown');
+
+    this._bridge.removeAllListeners();
+    this.removeAllListeners();
   };
 
   startProfiling: (recordChangeDescriptions: boolean) => void =
diff --git a/packages/react-devtools-shared/src/backend/fiber/renderer.js b/packages/react-devtools-shared/src/backend/fiber/renderer.js
index 9732bf105ca6c..c9d6922854902 100644
--- a/packages/react-devtools-shared/src/backend/fiber/renderer.js
+++ b/packages/react-devtools-shared/src/backend/fiber/renderer.js
@@ -3472,7 +3472,7 @@ export function attach(
   }
 
   function cleanup() {
-    // We don't patch any methods so there is no cleanup.
+    isProfiling = false;
   }
 
   function rootSupportsProfiling(root: any) {
diff --git a/packages/react-devtools-shared/src/backend/index.js b/packages/react-devtools-shared/src/backend/index.js
index 86714b7f61476..ace5dbc8c03ce 100644
--- a/packages/react-devtools-shared/src/backend/index.js
+++ b/packages/react-devtools-shared/src/backend/index.js
@@ -80,15 +80,12 @@ export function initBackend(
     });
     hook.reactDevtoolsAgent = null;
   };
-  agent.addListener('shutdown', onAgentShutdown);
-  subs.push(() => {
-    agent.removeListener('shutdown', onAgentShutdown);
-  });
 
+  // Agent's event listeners are cleaned up by Agent in `shutdown` implementation.
+  agent.addListener('shutdown', onAgentShutdown);
   agent.addListener('updateHookSettings', settings => {
     hook.settings = settings;
   });
-
   agent.addListener('getHookSettings', () => {
     if (hook.settings != null) {
       agent.onHookSettings(hook.settings);