In Cloudflare Workers, a ROUTE is used to define which incoming HTTP requests should be handled by a specific Worker script. It acts as a pattern-matching rule that determines when and where the Worker should be executed based on the URL of the request. By setting up ROUTEs, you can specify that certain paths or subdomains trigger the Worker, allowing you to apply custom logic, modify requests and responses, or serve dynamic content for specific parts of your website or application.