U.S. Route 224 (US 224) is a spur of U.S. Route 24. It currently runs for 289 miles (465 km) from New Castle, Pennsylvania at U.S. Route 422 Business and Pennsylvania Route 18 to Huntington, Indiana at U.S. Route 24. It passes through the states of Pennsylvania, Ohio and Indiana. It goes through the cities of Youngstown, Ohio, Akron, Ohio, and Findlay, Ohio.

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

From the western terminus US 224 heads southeast concurrenct with State Road 5 (SR 5). US 224 and SR 5 heads through downtown Huntington as one-way streets, with eastbound on Cherry Street and State Street and westbound on Warren Street. From downtown US 224 and SR 5 head southeast then outside of downtown SR 5 heads due south and US 224 heads east. US 224 passes through Markle where US 224 has an interchange with Interstate 69 (I-69) and intersections with both State Road 116 (SR 116) and State Road 3 (SR 3). US 224 heads east towards Decatur passing through intersections with State Road 301 (SR 301) and State Road 1 (SR 1). In Decatur US 224 has a short concurrency with U.S. Route 27 (US 27) and U.S. Route 33 (US 33). US 224 heads east from Decatur towards Ohio passing through a short concurrency with State Road 101 (SR 101).

The only section of U.S. Route 224 in Indiana that is included in the National Highway System (NHS) is the part concurrent with US 27 and US 33. The NHS is a network of highways that are identified as being most important for the economy, mobility and defense of the nation. The highway is maintained by the Indiana Department of Transportation (INDOT) like all other U.S. Highways in the state. The department tracks the traffic volumes along all state highways as a part of its maintenance responsibilities using a metric called average annual daily traffic (AADT). This measurement is a calculation of the traffic level along a segment of roadway for any average day of the year. In 2010, INDOT figured that lowest traffic levels were 2,420 vehicles and 670 commercial vehicles used the highway daily near the Ohio state line. The peak traffic volumes were 21,680 vehicles and 1,690 commercial vehicles AADT along the section of US 224 that is concurrent with US 27 and US 33.

West of its concurrence with US 42 near Lodi, Ohio, US 224 is a rural arterial highway, mostly two lanes, across western Ohio. It runs roughly parallel to the former Baltimore & Ohio Railroad from its westerly US 42 junction to Tiffin, Ohio, 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, Ohio, and goes through downtown Findlay and Ottawa, Ohio, but it otherwise specializes in small towns along its course across northwest Ohio. It crosses US 250 east of Greenwich, Ohio; Ohio Route 4 (a major north-south route) at Attica, Ohio; US 23 south of Fostoria, Ohio, and I-75 in Findlay, and has brief concurrences with US 127 and US 30 near Van Wert, Ohio. It crosses the Ashland Railway just east of Willard, the Norfolk Southern railroad at Attica, CSX Transportation near US 23, in Findlay, and in Ottawa, and the Chicago, Fort Wayne & Eastern west of Van Wert.

US 224 crosses into Mahoning Township in Lawrence County, Pennsylvania and becomes West State Street, a two-lane undivided road. The road heads through wooded areas with some homes and commercial establishments, heading to the east-southeast. The route curves to the northeast in Peanut and passes over a Norfolk Southern railroad line, coming to an intersection with PA 551. Here, PA 551 turns northeast to form a concurrency with US 224. The road heads through wooded areas and crosses the Mahoning River and two CSX railroad lines. PA 551 splits from US 224 by heading north on North Edinburg Road, with US 224 continuing into wooded areas with some farm fields. The road turns to the southeast and enters Union Township. 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 businesses 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. Past this interchange, the road becomes a three-lane road with a center left-turn lane and passes through a mix of residences and businesses, running through the community of Oakwood. The route heads into 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. The road heads to the east and continues through commercial areas. US 224 ends at an intersection with PA 18, at which point US 422 Business turns south to join that route.

When US 224 was commissioned in Indiana in 1934, it replace State Road 16 (SR 16), from Huntington to the Ohio state line.

Although U.S. 224 is only in Pennsylvania for 10 miles, the eastern terminus has changed several times since being issued in 1933, ending at various points in New Castle, Pennsylvania or in adjacent Union Township west of the city. The eastern terminus has been moved five times (1936, 1947, 1974, 1977, 2008), the most notable of which was in the 1970s when the New Castle Bypass opened in 1974 and saw an extension of U.S. 224 through the city itself and into Shenango Township at the eastern terminus of the bypass, essentially taking over U.S. 422's old alignment after 422 moved to the bypass.

The route was truncated back at the current interchange with 422 and Interstate 376 in 1977 while the old alignment through New Castle was replaced by Business 422. This would be the case until March 20, 2008, when 224 was officially extended two miles (3 km) to PA 18 inside the New Castle city limits with the placement of new signs. PennDOT had gotten approval from the AASHTO for the extension in September 2007.

The extension of U.S. 224 marked the second extension of a major highway into downtown New Castle in a little more than a year, as Pennsylvania Route 65 was extended a mile from its previous terminus with Business 422 to the PA 108/PA 168 concurrency in February 2007.