The highway begins from the south on Strawberry Avenue, at the intersection with the Del Perro Freeway in Textile City. It begins as a six lane urban freeway traveling through northeast, intersecting the Racetrack and the Vinewood Bowl. It then begins to turn north while narrowing to a rural four-lane freeway at the Route 18 interchange, as it skirts along the western edge of the Tataviam Mountains. This part is co-signed with Route 13. At the intersection of the Palomino Freeway, I-1 loses its concurrency, and the freeway continues as the Senora Freeway.
- The Los Santos Freeway is the only highway to cross universes.
- The Los Santos Freeway is mentioned in Grand Theft Auto IV on the radio station Public Liberty Radio. One of the guests states that he had a chase scene on the Los Santos Freeway.