Along the route, the highway runs concurrent with US 6, US 85 in the Denver metropolitan area, and US 34 from Wiggins to Fort Morgan.

The section of I-76 from its western terminus at I-70 to the SH 71 interchange near Brush, Colorado is designated as part of the Heartland Expressway, a planned series of multi-lane highways connecting Denver and Rapid City, South Dakota.

The combined routes of US 6 and I-76 head northeastward, crossing SH 2 south, named Sable Boulevard, before meeting an exit at E-470, a toll road.

Just south of the Empire Reservoir, the freeway turns back east, crossing into Morgan County within circular fields.

The freeway heads east toward Fort Morgan, spawning another business loop (I-76 Bus) that carries US 34 away from I-76.

The freeway heads east into Fort Morgan, meeting SH 52, now running again near the South Platte River.

Bypassing that city, I-76 traverses northeast into Washington County, with farms to the north along the river and grasslands to the south.

I-76 continues parallel to the South Platte River, surrounded by farms to the northwest and plains to the southeast.

Its entire route is located in Deuel County, parallel to the South Platte River and US 138.

Until 1974, both the segment of I-76 in Colorado and Nebraska and a portion of I-76 in Ohio, Pennsylvania, and New Jersey were signed as Interstate 80S (I-80S).

[1] In 1968, I-25 and US 85 were open to the general traffic to the Denver vicinity after all the structures located throughout the route were completed, as well as meeting the criteria of the Interstate standards.

The completion also included structures in which each cross the Burlington Canal, Platte River, and Union Pacific Railroad.

This 52.31-mile (84.18 km) route is the longest continuously signed Interstate business loop in the system.

Entering Brush, the route becomes Edison Street and passes toward the south of town, remaining parallel with the Interstate.

Then, I-76 Bus comes across a minor Y interchange and US 34 continues east while the business loop proceeds northeast.

The route continues northeast into Atwood and intersects SH 63, becoming Front Avenue toward 7th Street, remaining concurrent with US 6.

I-76 Bus meets I-76 and terminates there at a diamond interchange at exit 125, and US 6 continues east past the Interstate.