diff --git a/experimental/CHANGELOG.md b/experimental/CHANGELOG.md
index 256f3bfb2d4..23dd674543f 100644
--- a/experimental/CHANGELOG.md
+++ b/experimental/CHANGELOG.md
@@ -11,6 +11,8 @@ All notable changes to experimental packages in this project will be documented
 
 ### :bug: (Bug Fix)
 
+* fix(instrumentation): Fix wrapping ESM files with absolute path [#5094](https://github.com/open-telemetry/opentelemetry-js/pull/5094) @serkan-ozal
+
 ### :books: (Refine Doc)
 
 ### :house: (Internal)
diff --git a/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts b/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts
index b69e91dfebf..c99d52ea2c7 100644
--- a/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts
+++ b/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts
@@ -287,6 +287,11 @@ export abstract class InstrumentationBase<
     this._warnOnPreloadedModules();
     for (const module of this._modules) {
       const hookFn: HookFn = (exports, name, baseDir) => {
+        if (!baseDir && path.isAbsolute(name)) {
+          const parsedPath = path.parse(name);
+          name = parsedPath.name;
+          baseDir = parsedPath.dir;
+        }
         return this._onRequire<typeof exports>(module, exports, name, baseDir);
       };
       const onRequire: OnRequireFn = (exports, name, baseDir) => {
diff --git a/experimental/packages/opentelemetry-instrumentation/test/node/EsmInstrumentation.test.mjs b/experimental/packages/opentelemetry-instrumentation/test/node/EsmInstrumentation.test.mjs
index a46fdc0fd3e..3cea21cc698 100644
--- a/experimental/packages/opentelemetry-instrumentation/test/node/EsmInstrumentation.test.mjs
+++ b/experimental/packages/opentelemetry-instrumentation/test/node/EsmInstrumentation.test.mjs
@@ -18,8 +18,15 @@ import * as assert from 'assert';
 import {
   InstrumentationBase,
   InstrumentationNodeModuleDefinition,
+  InstrumentationNodeModuleFile,
 } from '../../build/src/index.js';
 import * as exported from 'test-esm-module';
+import * as exportedAbsolute from './esm/test.mjs';
+
+import path from 'path';
+import url from 'url';
+
+const TEST_DIR_NAME = path.dirname(url.fileURLToPath(import.meta.url));
 
 class TestInstrumentationWrapFn extends InstrumentationBase {
   constructor(config) {
@@ -95,6 +102,45 @@ class TestInstrumentationSimple extends InstrumentationBase {
     );
   }
 }
+
+class TestAbsoluteFileInstrumentationPatchFn extends InstrumentationBase {
+  constructor(config) {
+    super('test-esm-instrumentation', '0.0.1', config);
+  }
+  init() {
+    return new InstrumentationNodeModuleDefinition(
+      path.join(TEST_DIR_NAME, '/esm/test.mjs'),
+      ['*'],
+      undefined,
+      undefined,
+      [
+        new InstrumentationNodeModuleFile(
+          'test',
+          ['*'],
+          moduleExports => {
+            const wrapRetval = this._wrap(moduleExports, 'testFunction', () => {
+              return function wrappedTestFunction() {
+                return 'patched';
+              };
+            });
+            assert.strictEqual(typeof wrapRetval, 'function');
+            assert.strictEqual(
+              wrapRetval.name,
+              'wrappedTestFunction',
+              '_wrap(..., "testFunction", ...) return value is the wrapped function'
+            );
+            return moduleExports;
+          },
+          moduleExports => {
+            this._unwrap(moduleExports, 'testFunction');
+            return moduleExports;
+          }
+        )
+      ]
+    )
+  }
+}
+
 describe('when loading esm module', () => {
   const instrumentationWrap = new TestInstrumentationWrapFn({
     enabled: false,
@@ -140,4 +186,23 @@ describe('when loading esm module', () => {
     assert.deepEqual(exported.testFunction(), 'original');
     assert.deepEqual(exported.secondTestFunction(), 'original');
   });
+
+  it('should patch function from a file with absolute path', async () => {
+    const instrumentation = new TestAbsoluteFileInstrumentationPatchFn({
+      enabled: false,
+    });
+    instrumentation.enable();
+    assert.deepEqual(exportedAbsolute.testFunction(), 'patched');
+  });
+
+  it('should unwrap a patched function from a file with absolute path', async () => {
+    const instrumentation = new TestAbsoluteFileInstrumentationPatchFn({
+      enabled: false,
+    });
+
+    instrumentation.enable();
+    // disable to trigger unwrap
+    instrumentation.disable();
+    assert.deepEqual(exported.testFunction(), 'original');
+  });
 });
diff --git a/experimental/packages/opentelemetry-instrumentation/test/node/esm/test.mjs b/experimental/packages/opentelemetry-instrumentation/test/node/esm/test.mjs
new file mode 100644
index 00000000000..56e1af29552
--- /dev/null
+++ b/experimental/packages/opentelemetry-instrumentation/test/node/esm/test.mjs
@@ -0,0 +1,3 @@
+export const testFunction = () => {
+  return 'original';
+};