diff --git a/experimental/packages/opentelemetry-instrumentation-fetch/src/fetch.ts b/experimental/packages/opentelemetry-instrumentation-fetch/src/fetch.ts
index cf8b97b6986..03819704621 100644
--- a/experimental/packages/opentelemetry-instrumentation-fetch/src/fetch.ts
+++ b/experimental/packages/opentelemetry-instrumentation-fetch/src/fetch.ts
@@ -55,6 +55,7 @@ import {
 import { FetchError, FetchResponse, SpanData } from './types';
 import {
   getFetchBodyLength,
+  isRequest,
   normalizeHttpRequestMethod,
   serverPortFromUrl,
 } from './utils';
@@ -215,7 +216,7 @@ export class FetchInstrumentation extends InstrumentationBase<FetchInstrumentati
       return;
     }
 
-    if (options instanceof Request) {
+    if (isRequest(options)) {
       propagation.inject(context.active(), options.headers, {
         set: (h, k, v) => h.set(k, typeof v === 'string' ? v : String(v)),
       });
@@ -395,10 +396,10 @@ export class FetchInstrumentation extends InstrumentationBase<FetchInstrumentati
       ): Promise<Response> {
         const self = this;
         const url = web.parseUrl(
-          args[0] instanceof Request ? args[0].url : String(args[0])
+          isRequest(args[0]) ? args[0].url : String(args[0])
         ).href;
 
-        const options = args[0] instanceof Request ? args[0] : args[1] || {};
+        const options = isRequest(args[0]) ? args[0] : args[1] || {};
         const createdSpan = plugin._createSpan(url, options);
         if (!createdSpan) {
           return original.apply(this, args);
@@ -568,7 +569,7 @@ export class FetchInstrumentation extends InstrumentationBase<FetchInstrumentati
               return original
                 .apply(
                   self,
-                  options instanceof Request ? [options] : [url, options]
+                  isRequest(options) ? [options] : [url, options]
                 )
                 .then(
                   onSuccess.bind(self, createdSpan, resolve),
diff --git a/experimental/packages/opentelemetry-instrumentation-fetch/src/utils.ts b/experimental/packages/opentelemetry-instrumentation-fetch/src/utils.ts
index fb8b4dd37cd..a5da6b9d72d 100644
--- a/experimental/packages/opentelemetry-instrumentation-fetch/src/utils.ts
+++ b/experimental/packages/opentelemetry-instrumentation-fetch/src/utils.ts
@@ -25,6 +25,33 @@ const DIAG_LOGGER = diag.createComponentLogger({
   namespace: '@opentelemetry/opentelemetry-instrumentation-fetch/utils',
 });
 
+export function isRequest(value: unknown): value is Request {
+  if (value === null || typeof value !== 'object') {
+    return false;
+  }
+
+  const candidate = value as {
+    url?: unknown;
+    method?: unknown;
+    headers?: unknown;
+    clone?: unknown;
+  };
+
+  const headers = candidate.headers as
+    | { get?: unknown; set?: unknown }
+    | undefined;
+
+  return (
+    typeof candidate.url === 'string' &&
+    typeof candidate.method === 'string' &&
+    typeof candidate.clone === 'function' &&
+    typeof headers === 'object' &&
+    headers !== null &&
+    typeof headers.get === 'function' &&
+    typeof headers.set === 'function'
+  );
+}
+
 /**
  * Helper function to determine payload content length for fetch requests
  *
@@ -67,9 +94,9 @@ export function getFetchBodyLength(...args: Parameters<typeof fetch>) {
     } else {
       return Promise.resolve(getXHRBodyLength(requestInit.body));
     }
-  } else {
+  } else if (isRequest(args[0])) {
     const info = args[0];
-    if (!info?.body) {
+    if (!info.body) {
       return Promise.resolve();
     }
 
@@ -77,6 +104,8 @@ export function getFetchBodyLength(...args: Parameters<typeof fetch>) {
       .clone()
       .text()
       .then(t => getByteLength(t));
+  } else {
+    return Promise.resolve();
   }
 }
 
@@ -214,7 +243,7 @@ function getKnownMethods() {
     );
     if (cfgMethods && cfgMethods.length > 0) {
       knownMethods = {};
-      cfgMethods.forEach(m => {
+      cfgMethods.forEach((m: string) => {
         knownMethods[m] = true;
       });
     } else {
diff --git a/experimental/packages/opentelemetry-instrumentation-fetch/test/fetch.test.ts b/experimental/packages/opentelemetry-instrumentation-fetch/test/fetch.test.ts
index e75bbf0b1f3..a40f6ce634c 100644
--- a/experimental/packages/opentelemetry-instrumentation-fetch/test/fetch.test.ts
+++ b/experimental/packages/opentelemetry-instrumentation-fetch/test/fetch.test.ts
@@ -42,6 +42,7 @@ import {
   FetchInstrumentation,
   FetchInstrumentationConfig,
 } from '../src';
+import { isRequest as isRequestLike } from '../src/utils';
 import { AttributeNames } from '../src/enums/AttributeNames';
 import {
   ATTR_HTTP_HOST,
@@ -1750,7 +1751,7 @@ describe('fetch', () => {
           config: {
             requestHook: (span, request) => {
               assert.ok(
-                request instanceof Request,
+                isRequestLike(request),
                 '`requestHook` should get the `Request` object passed to `fetch()`'
               );
 
@@ -1779,6 +1780,53 @@ describe('fetch', () => {
         );
       });
 
+      it('treats a `Request` argument as a request even if global Request is overwritten', async () => {
+        const OriginalRequest = globalThis.Request;
+
+        try {
+          (globalThis as any).Request = function Request() {};
+
+          const { response } = await tracedFetch({
+            config: {
+              requestHook: (span, request) => {
+                assert.ok(
+                  isRequestLike(request),
+                  '`requestHook` should get the `Request` object passed to `fetch()`'
+                );
+
+                assert.ok(
+                  !((request as any) instanceof Request),
+                  'sanity check: `instanceof Request` should fail when global Request is overwritten'
+                );
+
+                (request as Request).headers.set('custom-foo', 'foo');
+              },
+            },
+            callback: () =>
+              fetch(
+                new OriginalRequest('/api/echo-headers.json', {
+                  headers: new Headers({ 'custom-bar': 'bar' }),
+                })
+              ),
+          });
+
+          const { request } = await response.json();
+
+          assert.strictEqual(
+            request.headers['custom-foo'],
+            'foo',
+            'header set from requestHook should be sent'
+          );
+          assert.strictEqual(
+            request.headers['custom-bar'],
+            'bar',
+            'header set from fetch() should be sent'
+          );
+        } finally {
+          globalThis.Request = OriginalRequest;
+        }
+      });
+
       it('can modify headers when called with a `RequestInit` object', async () => {
         const { response } = await tracedFetch({
           config: {