Prior to 1984, the highway left the state in Omaha as it traveled east through the city along the present-day I-480/US 6 corridor across the Missouri River into Iowa.

After crossing the south and north forks of the Big Nemaha River the highway enters Dawson a small village founded as Noraville in 1872 along the Atchison and Nebraska Railroad.

The highway then makes a sweeping turn to jog one mile (1.6 km) west before resuming a northerly course as it approaches an intersection with N-4.

Continuing due north, US 75 travels 10 miles (16 km) through the rolling hills of eastern Nebraska before entering the city of Auburn.

From this point, continuing north, US 75 generally runs parallel to, and within 10 miles (16 km) of the Missouri River for the duration of length.

Continuing north, the concurrent highways travel west of Beaver Lake, then come to a junction with N-66 on the southwest side of Plattsmouth.

The highway crosses the Platte River then comes to an interchange where US 34 departs to the east along the aforementioned new alignment while US 75 continues north into Bellevue.

As the highway passes Chandler Road and bends to the northwest it crosses over the railroad before becoming a depressed freeway just before its interchange with Q Street.

Opened in 2010, it's a seven building, 16-acre (6.5 ha) mixed-use development containing luxury condominiums, apartments, and more than 225,000 square feet (20,900 m2) of dining, entertainment, and shopping.

As US 75 continues north beyond the Omaha City Limits, the highway winds its way through rolling hills before entering the Missouri River plain just south of Fort Calhoun.

The highway continues north out of Tekamah, still following the edge of the rolling hills and Missouri River plain passing through rich agricultural fields, for 15 miles (24 km) before coming to an intersection with N-51 on the south edge of Decatur just west of the Onawa Materials Yard and Middle Decatur Bend State Wildlife Areas, both enclaves of Nebraska that are situated on the eastern side of the Missouri River and are only accessible via roads in Iowa.

US 75 and N-51 run concurrently through Decatur for one-half mile (800 m) before N-51 departs to the east to cross the Missouri River into Iowa while US 75 continues north out of town.

Heading out of Decatur, the highway climbs back into the rolling hills as it turns northwest into the Omaha Reservation towards the tribal seat of Macy.

Here the two highways run concurrently to the north as they emerge from the rolling hills back into the Missouri River plain as they pass through the village of Homer.

US 75 joins I-129 and US 20 to head east across the southern portion of South Sioux City to the Sergeant Floyd Memorial Bridge which crosses the Missouri River and continues into Iowa.

As they traveled northwest along the Missouri River the expedition would set up camp at sites on land in present-day Nebraska at several locations.

Many of these campsites are recognized by monuments established by the Nebraska Historical Society along the US 75 corridor near the towns of Rulo, Brownville, Plattsmouth, Omaha, Fort Calhoun, Blair, and Jackson.

At this same time, US 73 entered Nebraska south of Falls City and ran north through Shubert and Howe before terminating at an intersection with US 75.

[23] In 1984, proposals to AASHTO by the Nebraska Department of Roads recommended truncating the designation of US 73 on its northern end back to Dawson.

In 1976, the Department of Roads applied to the American Association of State Highway and Transportation Officials to assign this route as Interstate 580.