State Trunk Highway 121 (often called Highway 121, STH-121 or WIS 121) is a 45.07-mile (72.53 km) state highway in Buffalo, Trempealeau, and Jackson counties in the west-central area of the US state of Wisconsin that runs east–west from Gilmanton to near Alma Center.

Starting at WIS 88 in Gilmanton, WIS 121 starts to travel eastward, passing through Lookout and Russell.

Then, in Whitehall, WIS 121 begins to run concurrently with US Highway 53 (US 53).

Then, in Pigeon Falls, WIS 121 branches eastward, passing through York and Northfield.

In Northfield, it then meets Interstate 94 (I-94) at a diamond interchange.