The freeway serves the Reno metropolitan area and passes through the towns of Fernley, Lovelock, Winnemucca, Battle Mountain, Carlin, Elko, Wells, and West Wendover on its way through the state.

I-80 enters Nevada in the canyon of the Truckee River, paralleling the California Trail and first transcontinental railroad.

Upon exiting the canyon, the freeway serves the Truckee Meadows, a name for the urban area consisting of Verdi, Reno, and Sparks.

After leaving the Reno metropolitan area, the freeway resumes following the Truckee River in a canyon to Fernley and passes the Northern Nevada Veterans Cemetery to the north.

At Winnemucca, I-80 is joined by the Feather River Route; I-80 runs parallel to this railroad until the Utah state line.

Between Winnemucca and Battle Mountain, the freeway bypasses bends via side canyons and Golconda Summit, 5,159 feet (1,572 m).

From the Utah state line west to the Humboldt River, I-80 follows a modified routing of a lesser used branch of the trail called Hastings Cutoff.

Through this portion of Nevada, the main route of the California Trail ran north of modern SR 233.

The first transcontinental railroad, completed in 1869, closely follows the main line of the California Trail and I-80 west of Wells.

I-80 is also known in Nevada as the Dwight D. Eisenhower Highway after the former president of the same name and the Purple Heart Trail after such military decoration.

[11] There are plans to widen I-80 to three lanes in both directions from Vista Boulevard and Greg Street to SR 439 south (USA Parkway).

[13] This is due to the increase in traffic travelling between Reno and Sparks to the Industrial Area built up on USA Parkway, thousands of people traverse I-80 through the Truckee River Canyon every day, and that section is still 2 lanes in each direction, and accidents on this stretch of Interstate have risen tremendously since the Industrial area has opened.