diff --git a/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts b/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts
index 70dac85332f..81455fde66d 100644
--- a/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts
+++ b/experimental/packages/opentelemetry-instrumentation/src/platform/node/instrumentation.ts
@@ -29,7 +29,7 @@ export abstract class InstrumentationBase<T = any>
   extends InstrumentationAbstract
   implements types.Instrumentation {
   private _modules: InstrumentationModuleDefinition<T>[];
-  private _hooks: RequireInTheMiddle.Hooked[] = [];
+  private _hooked = false;
   private _enabled = false;
 
   constructor(
@@ -142,7 +142,7 @@ export abstract class InstrumentationBase<T = any>
     this._enabled = true;
 
     // already hooked, just call patch again
-    if (this._hooks.length > 0) {
+    if (this._hooked) {
       for (const module of this._modules) {
         if (typeof module.patch === 'function' && module.moduleExports) {
           module.patch(module.moduleExports, module.moduleVersion);
@@ -158,22 +158,20 @@ export abstract class InstrumentationBase<T = any>
 
     this._warnOnPreloadedModules();
     for (const module of this._modules) {
-      this._hooks.push(
-        RequireInTheMiddle(
-          [module.name],
-          { internals: true },
-          (exports, name, baseDir) => {
-            return this._onRequire<typeof exports>(
-              (module as unknown) as InstrumentationModuleDefinition<
-                typeof exports
+      requireInTheMiddleSingleton.register(
+        module.name,
+        (exports, name, baseDir) => {
+          return this._onRequire<typeof exports>(
+            (module as unknown) as InstrumentationModuleDefinition<
+              typeof exports
               >,
-              exports,
-              name,
-              baseDir
-            );
-          }
-        )
+            exports,
+            name,
+            baseDir
+          );
+        }
       );
+      this._hooked = true;
     }
   }
 
@@ -210,3 +208,52 @@ function isSupported(supportedVersions: string[], version?: string, includePrere
     return satisfies(version, supportedVersion, { includePrerelease });
   });
 }
+
+/**
+ * Singleton class for `require-in-the-middle`
+ * Allows instrumentation plugins to patch modules with only a single `require` patch
+ * TODO: Move this to a higher level to ensure it is a singleton across the Node.js process
+ */
+class RequireInTheMiddleSingleton {
+  private _modulesToHook: Array<{ moduleName: string, onRequire: RequireInTheMiddle.OnRequireFn }> = [];
+
+  constructor() {
+    this._initialize();
+  }
+
+  private _initialize() {
+    RequireInTheMiddle(
+      // Intercept all `require` calls; we will filter the matching ones below
+      null,
+      { internals: true },
+      (exports, name, baseDir) => {
+        const matches = this._modulesToHook.filter(({ moduleName: hookedModuleName }) => {
+          return RequireInTheMiddleSingleton._shouldHook(hookedModuleName, name, baseDir);
+        });
+
+        for (const { onRequire } of matches) {
+          exports = onRequire(exports, name, baseDir);
+        }
+
+        return exports;
+      }
+    );
+  }
+
+  private static _shouldHook(hookedModuleName: string, requiredModuleName: string, requiredModuleBaseDir: string | undefined) {
+    if (path.isAbsolute(hookedModuleName)) {
+      if (requiredModuleBaseDir === undefined) {
+        return false;
+      }
+      requiredModuleName = path.resolve(requiredModuleBaseDir, requiredModuleName);
+    }
+
+    return requiredModuleName === hookedModuleName || requiredModuleName.startsWith(hookedModuleName + path.sep);
+  }
+
+  register(moduleName: string, onRequire: RequireInTheMiddle.OnRequireFn) {
+    this._modulesToHook.push({ moduleName, onRequire });
+  }
+}
+
+const requireInTheMiddleSingleton = new RequireInTheMiddleSingleton();