The southern terminus of the route is situated at PA 120 in Emporium.

The northern terminus is located at the Bradford Bypass, carrying U.S. Route 219 (US 219) and PA 346, in Bradford, roughly two miles south of the New York-Pennsylvania border.

PA 46 was first signed in 1927, extending from U.S. Route 6 in Smethport north to US 219 in Bradford.

The route was extended southward to Emporium in 1928, when the eastern segment of Pennsylvania Route 47, which ran along present-day PA 46 from PA 120 in Emporium to US 6 in Smethport, was decommissioned after only one year of service.

Pennsylvania Route 46 Truck is a truck route that bypasses a weight-restricted bridge over the Pidgeon Hollow Run in Norwich Township, Pennsylvania.