To secure Twilio webhook URLs in Node.js, it is recommended to use HTTPS and HTTP authentication. Additionally, validating the X-Twilio-Signature header, which is a unique string generated by Twilio using the AuthToken as the key, can ensure that only Twilio is interacting with your endpoints. The Twilio Node.js helper library provides a `validateRequest` method to make this process easier, accepting the AuthToken, the X-Twilio-Signature header, the URL of the HTTP endpoint, and the included request parameters. By using this method, you can verify that incoming requests are coming from Twilio and not just a third party trying to access your infrastructure.