U.S. Route 169 currently runs for 966 miles (1,555 km) from the city of Virginia, Minnesota to Tulsa, Oklahoma at U.S. Route 64.

U.S. Highway 169 is a major south–north highway spanning 75.1 miles (120.9 km) in Oklahoma. The southern terminus for US-169 is Memorial Drive. The highway connects Tulsa, Oklahoma to the south with the Kansas state border to the north at South Coffeyville, Oklahoma. US-169 travels through Tulsa, Rogers, and Nowata counties.

US-169 has undergone several widening projects that have brought US-169 to freeway and expressway standards. The highway is two lanes between Talala, Oklahoma and South Coffeyville except for a short four lane portion north of Nowata, Oklahoma and ending at State Highway 28.

An Alternate US-169 passes through Nowata following the original path of US-169. The alternate route begins at the intersection of Choctaw Avenue and reconnects with US-169 south of Nowata at its intersection with Maple Street.

In January 2005, Oklahoma Department of Transportation began a $16.8 million widening project on a mile-long stretch of US-169 (officially named 'Pearl Harbor Memorial Expressway', although this name is rarely used by Tulsans) from Interstate 244 to Interstate 44. The project widened the highway from four to six lanes, adding one lane in each direction. The project was completed in April 2006. This stretch of US-169 is traveled by approximately 106,000 vehicles per day.

US-169 enters the state at Coffeyville as a two-lane road. A segment between Chanute and Iola is a freeway with fully controlled access, even though there is only one lane in each direction. US-169 runs concurrently with US-59 starting about four miles (6 km) south of Garnett and diverges northeast again immediately south of Garnett. The intersection immediately south of Garnett used to be a "braided" intersection with Stop and Yield signs. It was identified as a high crash location in 2001, and was rebuilt as a roundabout that opened in April 2006. The Kansas Department of Transportation is rebuilding or planning to rebuild several other rural intersections as roundabouts for increased safety. In Garnett, 6th Avenue (from US-169 to US-59 is also known as Business US 169. Going south, it veers off from US-169 about a mile and a half north of the US-169/US-59/K-31 roundabout intersection and travels west and south on 6th Avenue from US-169 to US-59/K-31 (Maple St.) before turning south onto US-59/K-31 and running concurrent with them, ending at the US-169/US-59/K-31 roundabout intersection. At Osawatomie the road becomes a full freeway; as well as, running concurrent with K-7. In southern Johnson County 169 becomes an expressway until its junction with Interstate 35 in Olathe.

From this point to the Missouri state line, US-169 alternates between freeways and surface streets. It follows Interstate 35 to Shawnee Mission Parkway in Overland Park, then travels east to Rainbow Blvd. US-169 then follows surface streets to its junction with Interstate 70 near downtown Kansas City. US-169 and I-70 enter Missouri together just after crossing the Kansas River.

US 169 exits Interstate 70 shortly after both roads enter Missouri via the Lewis and Clark Viaduct. It crosses the Missouri River by the Broadway Bridge and serves Kansas City Downtown Airport. At Route 9, US 169 becomes a freeway. It remains a freeway or expressway for the rest of its route through Kansas City and its suburbs. This segment is also known as Arrowhead Trafficway, although this road neither passes nor approaches Arrowhead Stadium.

At Smithville US 169 reverts to a two-lane rural highway. In St. Joseph, it forms most of the Belt Highway, a major commercial strip on the eastern edge of town. 169 angles northeastward out of St. Joseph, passing through many rural communities before exiting Missouri north of Grant City.

US 169 intersects Interstate 29 three times in Missouri: once in Gladstone, and twice in St. Joseph.

U.S. 169 enters Iowa just south of Redding. It junctions Interstate 80 near De Soto. It becomes an expressway at U.S. Route 20 south of Fort Dodge. At Iowa Highway 7 on the northwest side of Fort Dodge it becomes a 2-lane highway again. This is changing, however, as a two-phase, $11 million project began in the spring of 2010 to widen the route to four lanes from Fort Dodge to Humboldt. U.S. 169 passes through Humboldt and Algona before it leaves Iowa north of Lakota.

U.S. 169 is a major north–south route in Minnesota, connecting the Minnesota River valley with the Twin Cities and the Iron Range. Much of the route is built to expressway or freeway standards.

In Missouri, US 169 replaced Route 1 from Kansas City to St. Joseph, Route 4 from St. Joseph to Stanberry, and all of Route 29 from Stanberry to Iowa. The part of Route 1 north of Kansas City had been Route 33 south of and Route 50 north of Grayson from 1922 to 1926.

Prior to 2008, US 169 traveled east on I-435 in Lenexa and Overland Park, Kansas, and then it traveled north on Metcalf Avenue.

Prior to 1981, US 169 entered Minneapolis, Minnesota.

Three bannered routes of U.S. Route 169 exist, one each in Oklahoma, in Missouri, and in Iowa.

U.S. 169 has one banner route while in Oklahoma, US 169 Alternate. The alternate route travels through Nowata while the main highway bypasses the town. The alternate route is approximately 2.70 miles (4.35 km) long.

The entire route is in Nowata, Nowata County.

U.S. Route 169 Spur is a 0.5-mile (0.80 km) long route in Smithville, Missouri. The spur route follows an old alignment of US 169 into the city center of Smithville ending at Main Street. The entire route is in Smithville, Clay County.

U.S. Route 169 Business is a 3-mile (4.8 km) long business route in Fort Dodge, Iowa. The route was established in 1990 along former sections of Iowa Highway 7 (Iowa 7) and U.S. Route 20. Iowa 7 had recently been truncated to its current eastern end at U.S. Route 169 and US 20 had been rerouted onto a new freeway south of Fort Dodge. Since both routes had viaducts over the Des Moines River, officials in Fort Dodge wanted the Iowa Department of Transportation to maintain the bridges. Officially, the route is Iowa Highway 926, but it is only signed as Business US 169. The entire route is in Fort Dodge, Webster County.