diff --git a/.changeset/khaki-clowns-fly.md b/.changeset/khaki-clowns-fly.md
new file mode 100644
index 000000000..c08209888
--- /dev/null
+++ b/.changeset/khaki-clowns-fly.md
@@ -0,0 +1,5 @@
+---
+"openapi-fetch": patch
+---
+
+Replace `instanceof Function` with `typeof === 'function'` to fix form-urlencoded body serialization in environments with separate JavaScript realms (e.g., Jest with experimental VM modules). Also fixes missing `headers` parameter in the type definition for `defaultBodySerializer`.
diff --git a/packages/openapi-fetch/src/index.d.ts b/packages/openapi-fetch/src/index.d.ts
index 5bca81075..83b603188 100644
--- a/packages/openapi-fetch/src/index.d.ts
+++ b/packages/openapi-fetch/src/index.d.ts
@@ -322,7 +322,7 @@ export declare function createQuerySerializer<T = unknown>(
 export declare function defaultPathSerializer(pathname: string, pathParams: Record<string, unknown>): string;
 
 /** Serialize body object to string */
-export declare function defaultBodySerializer<T>(body: T): string;
+export declare function defaultBodySerializer<T>(body: T, headers?: HeadersOptions): T | string;
 
 /** Construct URL string from baseUrl and handle path and query params */
 export declare function createFinalURL<O>(
diff --git a/packages/openapi-fetch/src/index.js b/packages/openapi-fetch/src/index.js
index 4c7250fb0..9cb013480 100644
--- a/packages/openapi-fetch/src/index.js
+++ b/packages/openapi-fetch/src/index.js
@@ -627,7 +627,7 @@ export function defaultBodySerializer(body, headers) {
   }
   if (headers) {
     const contentType =
-      headers.get instanceof Function
+      typeof headers.get === "function"
         ? (headers.get("Content-Type") ?? headers.get("content-type"))
         : (headers["Content-Type"] ?? headers["content-type"]);
     if (contentType === "application/x-www-form-urlencoded") {
diff --git a/packages/openapi-fetch/test/common/request.test.ts b/packages/openapi-fetch/test/common/request.test.ts
index 6a836520e..e3a5a638b 100644
--- a/packages/openapi-fetch/test/common/request.test.ts
+++ b/packages/openapi-fetch/test/common/request.test.ts
@@ -1,5 +1,5 @@
 import { describe, expect, test, vi } from "vitest";
-import createClient, { type BodySerializer, type FetchOptions } from "../../src/index.js";
+import createClient, { type BodySerializer, defaultBodySerializer, type FetchOptions } from "../../src/index.js";
 import { createObservedClient, headersToObj } from "../helpers.js";
 import type { components, paths } from "./schemas/common.js";
 
@@ -278,6 +278,59 @@ describe("request", () => {
       expect(bodyUsed).toBe(true);
       expect(bodyText).toBe("key1=value1&key2=value2");
     });
+
+    test("`application/x-www-form-urlencoded` body with Headers instance", async () => {
+      const { bodyUsed, bodyText } = await fireRequestAndGetBodyInformation({
+        method: "POST",
+        fetchOptions: {
+          body: { key1: "value1", key2: "value2" },
+          headers: new Headers({ "Content-Type": "application/x-www-form-urlencoded" }),
+        },
+      });
+
+      expect(bodyUsed).toBe(true);
+      expect(bodyText).toBe("key1=value1&key2=value2");
+    });
+  });
+
+  describe("defaultBodySerializer", () => {
+    test("serializes to JSON by default", () => {
+      const body = { key1: "value1", key2: "value2" };
+      expect(defaultBodySerializer(body, undefined)).toBe(JSON.stringify(body));
+    });
+
+    test("serializes to URLSearchParams with plain object headers", () => {
+      const body = { key1: "value1", key2: "value2" };
+      const headers = { "Content-Type": "application/x-www-form-urlencoded" };
+      expect(defaultBodySerializer(body, headers)).toBe("key1=value1&key2=value2");
+    });
+
+    test("serializes to URLSearchParams with Headers instance", () => {
+      const body = { key1: "value1", key2: "value2" };
+      const headers = new Headers({ "Content-Type": "application/x-www-form-urlencoded" });
+      expect(defaultBodySerializer(body, headers)).toBe("key1=value1&key2=value2");
+    });
+
+    test("serializes to URLSearchParams with lowercase content-type header", () => {
+      const body = { key1: "value1", key2: "value2" };
+      const headers = new Headers({ "content-type": "application/x-www-form-urlencoded" });
+      expect(defaultBodySerializer(body, headers)).toBe("key1=value1&key2=value2");
+    });
+
+    test("works with Headers-like object that has get method", () => {
+      // Simulates cross-realm scenario where instanceof Function fails but typeof works
+      const body = { key1: "value1", key2: "value2" };
+      const headersLike = {
+        get: (name: string) => (name.toLowerCase() === "content-type" ? "application/x-www-form-urlencoded" : null),
+      };
+      expect(defaultBodySerializer(body, headersLike as any)).toBe("key1=value1&key2=value2");
+    });
+
+    test("returns FormData as-is", () => {
+      const formData = new FormData();
+      formData.append("key1", "value1");
+      expect(defaultBodySerializer(formData, undefined)).toBe(formData);
+    });
   });
 
   test("cookie header is preserved", async () => {