U.S. Route 42 (US 42) is an east–west United States highway that runs southwest–northeast for 350 miles (560 km) from Louisville, Kentucky to Cleveland, Ohio.

Interstate 71 (I-71) fully supplanted US 42 as an interurban highway in the early 1960s, relegating US 42 to its current role as an ordinary town-to-town surface road.

From here US 42 is a two lane road passing through the northern Kentucky hills paralleling between Interstate 71 and the Ohio River.

Heading east US 42 parallels the Ohio River passing through Warsaw, Gallatin County about 5 miles (8.0 km) prior to intersecting with US 127 starting an extended concurrency.

US 42 enters Boone County about 2.25 miles (3.62 km) prior to intersecting with the western terminus of Kentucky Route 14 (KY 14).

It is classified as 59.3% rural and 40.7% urban, with only 1.1 miles (1.8 km) coded as freeway (while running concurrently with US 23 in Delaware).

[5] The route begins in Cincinnati, then passes through Hamilton, Butler, Warren, Greene, Clark, Madison, Union, Delaware, Morrow, Richland, Ashland, Wayne and Medina, Cuyahoga counties prior to reaching its terminus in Cleveland.

In 2020, the Cincinnati City Council approved a project to rename Reading Road to President Barack Obama Avenue from Downtown Cincinnati to Reading, pending private donations;[7][8] all 30,000 signs are expected to be installed by September 2021.

[11] The portion of US 42 in Warren County between Lebanon and Waynesville is designated "Sergeant Brian Dulle Memorial Highway",[12] in honor of a Warren County Sheriff's deputy who was struck and killed along US 42 on May 10, 2011, by a stolen car, while he was laying out stop sticks to catch the driver.

[16][17][18][19] In Xenia, the designation "Brigadier General Charles Young Memorial Historical Corridor"[20] leaves US 68 and joins US 42 at the routes' junction, in honor of Young, a pioneering figure in US history, and at his death, the highest-ranking Black officer in the Regular Army.

[25][26][27][28] After Wilberforce, major cities along the route are London, Delaware, Mansfield, Ashland and Medina prior to reaching the Cleveland metropolitan area.

The route is part of the Ohio & Erie Canalway Scenic Byway while continuing north on West 25th.

Along this stretch of the route, can be found many historic buildings, including the West Side Market.

The eastern/northern end of US 42 finds its terminus at the intersection of Superior Avenue and Ontario Street in the middle of Public Square in downtown Cleveland.