In the U.S. State of Nebraska, U.S. Highway 75 is a highway which goes from the Kansas border south of Dawson in the south to the Iowa border in the north at South Sioux City. Portions of the highway are freeway within the Omaha metropolitan area, including an overlap with Interstate 480. Another segment is freeway in the South Sioux City area, an overlap with Interstate 129. Much of the highway parallels the Missouri River.

U.S. Highway 75 begins at the Kansas border in Richardson County. It intersects Nebraska Highway 8 and then passes through Dawson. North of Dawson, it intersects U.S. Highway 73, Nebraska Highway 4, and Nebraska Highway 62. It continues north into Auburn, where it intersects U.S. Highway 136. It then overlaps Nebraska Highway 67 and intersects Nebraska Highway 128, where the highway becomes a divided highway. It continues as a divided highway until it intersects Nebraska Highway 2 in Nebraska City. It turns west with Nebraska Highway 2 and then turns north at the west end of Nebraska City. It intersects U.S. Highway 34 near Union. The two highways then intersect Nebraska Highway 1 near Murray before the overlap ends in Plattsmouth at their intersection with Nebraska Highway 66. Just north of Plattsmouth, the highway becomes divided again and crosses the Platte River.

After crossing the Platte River, U.S. Highway 75 becomes the Kennedy Freeway at its interchange with Fort Crook Road and Fairview Road. It then enters Bellevue, and has four interchanges in Bellevue, including one with Nebraska Highway 370. U.S. Highway 75 then enters Omaha in the South Omaha neighborhood. It then has three interchanges, including one with U.S. Highway 275 and Nebraska Highway 92, before intersecting Interstate 80 and beginning a new overlap with Interstate 480. The overlap continues north until they separate near downtown Omaha. U.S. Highway 75 then continues north on the North Freeway as it passes through North Omaha. The freeway then ends and the highway curves towards North 30th Street. It follows North 30th Street through the Florence neighborhood before turning west. It continues west until intersecting Nebraska Highway 36 and turning north. It then immediately intersects Interstate 680.

The highway continues north through Nashville and Fort Calhoun before entering Blair. In Blair, it intersects U.S. Highway 30 and overlaps in Blair. The overlap ends when they intersect Nebraska Highway 91, when U.S. Highway 75 turns north. It goes northwesterly through Herman, then turns north to Tekamah, where it intersects Nebraska Highway 32. It continues north to Decatur, where there is a short overlap with Nebraska Highway 51. It then turns northwest to enter the Omaha Indian Reservation. It then passes through Macy and intersects Nebraska Highway 94 before entering the Winnebago Indian Reservation. U.S. Highway 75 then intersects U.S. Highway 77 before entering Winnebago and leaving the Winnebago Indian Reservation. The two highways continue north through Homer, then turn northeast until at Dakota City, they intersect Nebraska Highway 35. They continue north until the intersection with U.S. Highway 20 and Interstate 129 at South Sioux City. U.S. Highway 75 then overlap U.S. 20 and I-129 eastward until crossing the Missouri River and entering Iowa.

In 1926, when the highway was created, U.S. Highway 75 went north from Kansas to Omaha, then turned east and crossed the Missouri River to enter Council Bluffs, Iowa. In 1985, U.S. 75 was rerouted to go west of the river between Omaha and Sioux City, Iowa, and U.S. 75 took over the former route of U.S. 73.

Construction of the North Omaha Freeway, coupled with social unrest in the 1970s, greatly changed the North Omaha area. One neighborhood experienced a 30 percent housing loss and major increase in crime. Interstate 580 (abbreviated I-580) was the original designation for this 4-mile (6.4 km) portion of US-75 during the late 1970s and early 1980s. This designation was revoked when the state of Nebraska declined to upgrade the interchange with I-480 to Interstate Highway standards, and the freeway is now solely US-75.

In 2005, the Nebraska Department of Roads began a project to bring the I-480/US-75 interchange up to Interstate standards. Construction was expected to be complete in 2009, but it has been delayed to 2011 due to shortage of funding.