In the U.S. State of Nebraska, U.S. Highway 6 is a highway which goes from the Colorado border west of Imperial in the west to the Iowa border in the east at Omaha. Significant portions of the highway are concurrent with other highways, most significantly, U.S. Highway 34 between Culbertson and Hastings. Also, from Milford east to the Iowa border, the highway is closely paralleled by Interstate 80.

U.S. Highway 6 enters Nebraska from Colorado west of Imperial on a short southeasterly segment. It turns east and stays due east until shortly before Imperial. It then goes into Imperial and meets Nebraska Highway 61. The two routes are paired together until they separate at the Enders Reservoir State Recreation Area. It goes in a generally southeasterly direction until it meets U.S. Highway 34 west of Culbertson.

US 6 and US 34 continue east together through Culbertson and at McCook, is briefly concurrent with U.S. Highway 83. US 6/34 continue together in a northeasterly direction through Cambridge, then turns due east and meets U.S. Highway 283 in Arapahoe. Near Edison, it meets U.S. Highway 136, which begins at its intersection with US 6/34. Further east, the two highways meet Nebraska Highway 4 and turns northeast towards Holdrege, Nebraska. In Holdrege, US 6/34 meet U.S. Highway 183. The highways continue on a northeasterly trajectory through Minden until Heartwell. At Heartwell, US 6/34 turns due east until Hastings. In Hastings, US 6/34 meet U.S. Highway 281 and US 34 separates to go with US 281 while US 6 continues eastward.

US 6 continues on a due east highway from Hastings. Near Sutton, the highway turns northeast to go through Sutton. It continues east and at Fairmont, US 6 encounters U.S. Highway 81. After passing through Friend, US 6 meets Nebraska Highway 15 and the two highways overlap until shortly before Milford. US 6 goes east, then north out of Milford, then US 6 turns east to go towards Lincoln.

In Lincoln, US 6 comes into the city on West O Street, portions of which are divided highway. At Sun Valley Boulevard, it turns to go northeasterly. At 10th Street, it turns north and is a divided highway. At Cornhusker Highway, it turns east, with a short connection to Interstate 180. It follows Cornhusker Highway, which is a divided highway, east out of the city. At the east end of Cornhusker Highway in Lincoln, US 6 meets Interstate 80.

From Interstate 80, US 6 goes northeast through Waverly, Greenwood and Ashland. East of Ashland, US 6 crosses the Platte River. After that, US 6 meets Nebraska Highway 31 in Gretna, where US 6 turns north with NE 31 on a divided highway. US 6/NE 31 meet U.S. Highway 275 and Nebraska Highway 92 near the Elkhorn neighborhood of Omaha and they separate in Elkhorn itself at a freeway interchange which also has Nebraska Link 28B, a connector to US 275.

US 6 goes onto the freeway at this point, which is West Dodge Road, and turns due east to go towards downtown Omaha. At 137th Street, there is an exit for Boys Town. Between 120th and 108th Streets, US 6 is an elevated freeway with separate viaducts for eastbound and westbound traffic. Shortly after this ends, US 6 meets Interstate 680. US 6 continues east and at Cass Street, turns briefly southeast. After US 6 meets Dodge Street, West Dodge Road ends and US 6 follows Dodge Street eastward. Before 30th Street, US 6 splits into two one way streets, with Dodge Street serving westbound traffic, and Douglas Street serving the eastbound. US 6 goes through downtown and then goes up onto Interstate 480, which is an elevated freeway around downtown Omaha, and shortly thereafter, crosses into Iowa via the Grenville Dodge Memorial Bridge.

When the U.S. Highway System was created in 1926, much of the current US 6 in Nebraska was U.S. Highway 38. The route was slightly different in the Omaha area, as it turned east from 204th Street onto Q Street to go through what was the city of Millard. It went through Millard on what is now Millard Avenue (Nebraska Highway 50), then north on 132nd Street, then east on Center Street, and then north on 36th Street to end at Farnam Street. In 1932, US 38 was deleted and replaced by US 6.

The cities of Hastings and Lincoln also had City U.S. Highway 6. These are former routes for US 6 in those cities. City US 6 in Hastings was deleted in 1970 and in Lincoln, it was deleted in 1983.