In Northeast Ohio, US 224 is located a short distance north of the Western Reserve's southern boundary.

It runs roughly parallel to the former Baltimore and Ohio Railroad from its westerly US 42 junction to Tiffin, a city around which it sweeps to the south with intersections at various state highways that radiate out from downtown.

US 224 passes through a commercial strip on the south side of Willard, and goes through downtown Findlay and Ottawa, but it otherwise specializes in small towns along its course across northwest Ohio.

US 224 crosses into Mahoning Township in Lawrence County, Pennsylvania, and becomes West State Street, a two-lane, undivided road.

The route curves to the northeast in Peanut and passes over Norfolk Southern's Youngstown Line, coming to an intersection with PA 551.

The road heads through wooded areas and crosses the Mahoning River and CSX's New Castle Subdivision railroad line.

The route continues through wooded areas with some farmland and homes, passing to the south of New Castle Municipal Airport and heading through the community of Parkstown.

US 224 heads into commercial areas, gaining a second lane westbound before widening into a six-lane divided highway as it comes to an interchange with I-376/US 422.

The route heads into the city of New Castle and passes through wooded areas of development, gaining a second westbound lane and coming to an intersection with US 422 Business.

At this point, US 422 Business turns east to join US 224 on four-lane divided West Falls Street, passing more development and crossing over a New Castle Industrial Railroad line and the Shenango River.

[4][5] US 224 was assigned to a portion of the Benjamin Franklin Highway, an auto trail running from Omaha, Nebraska to Philadelphia, Pennsylvania; its number assignment was an alternative to a westward rerouting of US 422 which runs along the Benjamin Franklin Highway farther east.

This would be the case until March 20, 2008, when US 224 was officially extended two miles (3.2 km) to PA 18 inside the New Castle city limits with the placement of new signs.