Most of its flow is underground, while its surface channels remain dry most of the time, except for the headwaters and several bedrock gorges in the lower reaches.

A desert branch of the Serrano Native Americans called the Vanyume or Beñemé, as Father Garcés called them, lived beyond and along much of the length of the Mojave River, from east of Barstow to at least the Victorville region, and perhaps even farther upstream to the south, for up to 8,000 years in a series of villages, including the major village of Wá'peat.

In 1826 Jedediah Smith was the first non-Native American to travel overland to California by following the Mojave Indian Trail.

A pack horse and livestock trail, the Old Spanish Trail, was established by Antonio Armijo in 1829 between New Mexico and El Pueblo de Los Ángeles, joined the Mojave River at its mouth near what is now Soda Lake.

In 1830, Wolfskill and Yount pioneered what became the Main Route of the Old Spanish Trail, which followed a different route than Armijo, farther south just west of the Colorado River and then followed Jedediah Smith's path on the old Mohave Trail west to the Mojave River mouth at Soda Lake, to meet with Armijo's route coming south from Salt Spring.

John C. Frémont intercepted this route to the river, riding east southeast from Lake Elizabeth, north of the foot of the San Gabriel Mountains on April 20, 1844.

It then followed the river to Soda Lake, where the road turned eastward to Fort Mojave, and in 1862 following the gold and silver strikes on the Colorado River, to Hardyville and the mining districts near it, and its connection at the head of the toll road to Prescott and the mines in the interior of Arizona Territory.

Downstream of the dam, the Mojave River flows north and east, underground in most places, through Hesperia, Victorville, and Barstow.

For example, during a heavy El Niño in the Mojave Desert, rains caused the Mojave River to overflow onto overpassing bridges on February 22, 1993, the most damaged being on Bear Valley Road, where Victorville and Apple Valley are separated.