It passes through the eastern fringe of the Inland Empire metropolitan area, going east from its western terminus at I-15 in Barstow across the Mojave Desert in San Bernardino County past the Clipper Mountains to Needles, before it crosses over the Colorado River into Arizona east of Needles.

The freeway passes through Marine Corps Logistics Base Barstow before leaving the city limits.

Several miles east of the preserve, I-40 intersects U.S. Route 95 (US 95), and the two highways run concurrently into the city of Needles.

[12][13] The section between Ludlow and Needles was constructed using conventional explosives and excavation and designed with culverts for migrating Bighorn sheep and water tanks.

[14] A sign at that start of I-40 in Barstow showing the distance to Wilmington, North Carolina, had been stolen multiple times.