The stretch of I-80 between mile markers 6 - 28 is known as the Three Sisters, which some refer to as the "Highway to Heaven" because of an optical illusion that makes it seem that the road is reaching toward the sky.

The highway meets the western end of WYO 374 south of Granger and has a trumpet interchange with US 30, which joins the Interstate in the first of several concurrencies east to Nebraska.

The Interstate has an interchange with Covered Wagon Road just west of its crossing of the Green River at James Town.

The business routes, here named Pilot Butte Avenue, rejoin I-80 and US 30 on the east side of the city.

[2] I-80 and US 30 continue east from Rock Springs parallel to the Union Pacific Railroad's Rawlins Subdivision and Bitter Creek.

The freeway has a junction with Continental Divide Road and an interchange with WYO 789, which joins the Interstate eastbound.

The Interstate has a trumpet interchange with Lincoln Avenue at the west end of Sinclair, then crosses over the railroad and WYO 76.

The Interstate has interchanges with Quealy Dome Road and WYO 12 (Herrick Lane) around its crossing of the Little Laramie River.

[2] A book, Snow Chi Minh Trail: The History of Interstate 80 between Laramie and Walcott Junction, was published by the Wyoming State Historical Society in 2017 describing the dangerous history of winter travel on the 77-mile (124 km) stretch of I-80 between exit 235 (near Rawlins and Hanna) and Laramie.

[4][5] Due to the numerous winter closures along this stretch, the Wyoming Department of Transportation (WYDOT) has proposed rerouting the highway to the north along US 30.

The two highways reach their national high point at Sherman Summit, where they have an interchange with WYO 210 (Happy Jack Road).

The Interstate and US Highways rejoin the railroad and pass through minor junctions with Remount, Harriman, and Warren roads.

The missing movement from the surface highway to eastbound I-80 is made via the business route's nearby interchange with I-25 and US 87.

[2] I-80 continues east across the Union Pacific Railroad to a full cloverleaf interchange with I-25 and US 87, where the highway enters the city of Cheyenne, the county seat and state capital.

The Interstate crosses over a BNSF Railway line and has a diamond interchange with US 85 and the southern end of I-180, a non-freeway spur into downtown Cheyenne.

East of its interchange with Campstool Road, the freeway leaves the city of Cheyenne and collects the eastern end of US 30 (Archer Boulevard).

I-80 and US 30 reapproach the Union Pacific Railroad's Sidney Subdivision east of Burns and parallel it to Pine Bluffs, the easternmost town in Wyoming.