diff --git a/CHANGELOG.md b/CHANGELOG.md
index 9c4b2f297a..82ad6fd838 100644
--- a/CHANGELOG.md
+++ b/CHANGELOG.md
@@ -13,6 +13,7 @@ For experimental package changes, see the [experimental CHANGELOG](experimental/
 
 ### :bug: (Bug Fix)
 
+* fix(http-instrumentation): stop listening to `request`'s `close` event once it has emitted `response` [#3625](https://github.com/open-telemetry/opentelemetry-js/pull/3625) @SimenB
 * fix(sdk-node): fix initialization in bundled environments by not loading @opentelemetry/exporter-jaeger [#3739](https://github.com/open-telemetry/opentelemetry-js/pull/3739) @pichlermarc
 
 ### :books: (Refine Doc)
diff --git a/experimental/packages/opentelemetry-instrumentation-http/src/http.ts b/experimental/packages/opentelemetry-instrumentation-http/src/http.ts
index 1f6affef66..0b5c166dd5 100644
--- a/experimental/packages/opentelemetry-instrumentation-http/src/http.ts
+++ b/experimental/packages/opentelemetry-instrumentation-http/src/http.ts
@@ -315,6 +315,11 @@ export class HttpInstrumentation extends InstrumentationBase<Http> {
       this._callRequestHook(span, request);
     }
 
+    /**
+     * Determines if the request has errored or the response has ended/errored.
+     */
+    let responseFinished = false;
+
     /*
      * User 'response' event listeners can be added before our listener,
      * force our listener to be the first, so response emitter is bound
@@ -323,6 +328,7 @@ export class HttpInstrumentation extends InstrumentationBase<Http> {
     request.prependListener(
       'response',
       (response: http.IncomingMessage & { aborted?: boolean }) => {
+        this._diag.debug('outgoingRequest on response()');
         const responseAttributes =
           utils.getOutgoingRequestAttributesOnResponse(response);
         span.setAttributes(responseAttributes);
@@ -344,9 +350,13 @@ export class HttpInstrumentation extends InstrumentationBase<Http> {
         );
 
         context.bind(context.active(), response);
-        this._diag.debug('outgoingRequest on response()');
-        response.on('end', () => {
+
+        const endHandler = () => {
           this._diag.debug('outgoingRequest on end()');
+          if (responseFinished) {
+            return;
+          }
+          responseFinished = true;
           let status: SpanStatus;
 
           if (response.aborted && !response.complete) {
@@ -381,15 +391,24 @@ export class HttpInstrumentation extends InstrumentationBase<Http> {
             startTime,
             metricAttributes
           );
-        });
+        };
+
+        response.on('end', endHandler);
+        // See https://github.com/open-telemetry/opentelemetry-js/pull/3625#issuecomment-1475673533
+        if (semver.lt(process.version, '16.0.0')) {
+          response.on('close', endHandler);
+        }
         response.on(errorMonitor, (error: Err) => {
           this._diag.debug('outgoingRequest on error()', error);
+          if (responseFinished) {
+            return;
+          }
+          responseFinished = true;
           utils.setSpanWithError(span, error);
-          const code = utils.parseResponseStatus(
-            SpanKind.CLIENT,
-            response.statusCode
-          );
-          span.setStatus({ code, message: error.message });
+          span.setStatus({
+            code: SpanStatusCode.ERROR,
+            message: error.message,
+          });
           this._closeHttpSpan(
             span,
             SpanKind.CLIENT,
@@ -401,12 +420,18 @@ export class HttpInstrumentation extends InstrumentationBase<Http> {
     );
     request.on('close', () => {
       this._diag.debug('outgoingRequest on request close()');
-      if (!request.aborted) {
-        this._closeHttpSpan(span, SpanKind.CLIENT, startTime, metricAttributes);
+      if (request.aborted || responseFinished) {
+        return;
       }
+      responseFinished = true;
+      this._closeHttpSpan(span, SpanKind.CLIENT, startTime, metricAttributes);
     });
     request.on(errorMonitor, (error: Err) => {
       this._diag.debug('outgoingRequest on request error()', error);
+      if (responseFinished) {
+        return;
+      }
+      responseFinished = true;
       utils.setSpanWithError(span, error);
       this._closeHttpSpan(span, SpanKind.CLIENT, startTime, metricAttributes);
     });
diff --git a/experimental/packages/opentelemetry-instrumentation-http/test/functionals/http-enable.test.ts b/experimental/packages/opentelemetry-instrumentation-http/test/functionals/http-enable.test.ts
index 5a5588993f..e5b2cebb97 100644
--- a/experimental/packages/opentelemetry-instrumentation-http/test/functionals/http-enable.test.ts
+++ b/experimental/packages/opentelemetry-instrumentation-http/test/functionals/http-enable.test.ts
@@ -16,11 +16,13 @@
 import {
   SpanStatusCode,
   context,
+  diag,
   propagation,
   Span as ISpan,
   SpanKind,
   trace,
   SpanAttributes,
+  DiagConsoleLogger,
 } from '@opentelemetry/api';
 import { NodeTracerProvider } from '@opentelemetry/sdk-trace-node';
 import {
@@ -269,6 +271,14 @@ describe('HttpInstrumentation', () => {
             // hang the request.
             return;
           }
+          if (request.url?.includes('/destroy-request')) {
+            // force flush http response header to trigger client response callback
+            response.write('');
+            setTimeout(() => {
+              request.socket.destroy();
+            }, 100);
+            return;
+          }
           if (request.url?.includes('/ignored')) {
             provider.getTracer('test').startSpan('some-span').end();
           }
@@ -861,11 +871,12 @@ describe('HttpInstrumentation', () => {
       });
 
       it('should have 2 ended span when client prematurely close', async () => {
-        const promise = new Promise<void>((resolve, reject) => {
+        const promise = new Promise<void>(resolve => {
           const req = http.get(
             `${protocol}://${hostname}:${serverPort}/hang`,
             res => {
               res.on('close', () => {});
+              res.on('error', () => {});
             }
           );
           // close the socket.
@@ -873,7 +884,7 @@ describe('HttpInstrumentation', () => {
             req.destroy();
           }, 10);
 
-          req.on('error', reject);
+          req.on('error', () => {});
 
           req.on('close', () => {
             // yield to server to end the span.
@@ -919,6 +930,41 @@ describe('HttpInstrumentation', () => {
         assert.strictEqual(clientSpan.status.code, SpanStatusCode.ERROR);
         assert.ok(Object.keys(clientSpan.attributes).length >= 6);
       });
+
+      it('should not end span multiple times if request socket destroyed before response completes', async () => {
+        const warnMessages: string[] = [];
+        diag.setLogger({
+          ...new DiagConsoleLogger(),
+          warn: message => {
+            warnMessages.push(message);
+          },
+        });
+        const promise = new Promise<void>(resolve => {
+          const req = http.request(
+            `${protocol}://${hostname}:${serverPort}/destroy-request`,
+            {
+              // Allow `req.write()`.
+              method: 'POST',
+            },
+            res => {
+              res.on('end', () => {});
+              res.on('close', () => {
+                resolve();
+              });
+              res.on('error', () => {});
+            }
+          );
+          // force flush http request header to trigger client response callback
+          req.write('');
+          req.on('error', () => {});
+        });
+
+        await promise;
+
+        diag.disable();
+
+        assert.deepStrictEqual(warnMessages, []);
+      });
     });
 
     describe('with require parent span', () => {