It enters the state from Oklahoma south of Chetopa and passes through Parsons, Ottawa, Oswego, Moran, Garnett, and Lawrence.

Most of the route climbs the cuestas of the Osage prairie,[2] while north of the Kansas River, it cuts through the glaciated region.

[6] KDOT surveys the roads under its control on a regular basis to measure the amount of traffic using the state's highways.

For the 2012 survey, the stretch of road with the highest AADT was 8,249 vehicles per day south of the Lawrence city limits.

Eight miles (13 km) to the north, it enters Oswego along Commerce Street where it crosses a line of the South Kansas & Oklahoma Railroad (SKOL).

These two routes head west together and then to the northwest parallel to a single Union Pacific Railroad (UP) track.

[7] Northwest of Oswego, the two routes follow a curve to north and then to the west, which allows a safe crossing of the UP line.

The concurrency with K-31 ends in northern Garnett, as K-31 forks to the west at Park Street and US-59 continues north and leaves the city.

Due to high accident rates, this stretch of US-59 was converted into a divided highway, with the project reaching completion in 2012.

Following this interchange, the freeway downgrades to an expressway with at-grade intersections, and the speed limit drops from 70 to 55 mph.

Prior to November 2016, K-10 was merged with US-59 between the South Lawrence Trafficway and 23rd Street due to lawsuits over the completion of the road.

Then the road turns sharply north and then due west, passing a local cemetery, before approaching the unincorporated community of Williamstown.

At this point, the two highways split off, with US-24 continuing west toward Perry and Topeka, while US-59 heads north toward Oskaloosa.

This stretch of US-59 is part of "The Iron Men Of Metz Highway", a designation running from Topeka to Leavenworth and including the segment of US-59 between Williamstown and its junction with K-16/K-92 just outside of Oskaloosa.

It forms the eastern terminus of K-4, then almost immediately has a junction with child route US-159, which heads north to Effingham.

US-59 continues east on its own through the rest of town and crosses the Amelia Earhart Memorial Bridge into Winthrop, Missouri, en route to St. Joseph.