The Indians of this region were great travelers. The Kawaiisu that lived in the Tehachapi Mountains to the north and west, almost certainly hunted in the area during certain seasons of the year. Other Indian groups lived in the San Gabriel Mountains south of the valley and were often to be found at Elizabeth Lake and other well-watered sites along the base of those mountains.

Mining and stock raising ventures were attempted by American and European settlers after about 1850, but the overall impact of these activities on the Antelope Valley remained minimal until 1876, when the railroad was built through the valley. Shortly thereafter, the towns of Lancaster, Palmdale, Rosamond, and others that didn't survive, sprang up and land speculation became rampant. A succession of wet years brought luxuriant stands of grass and incredibly beautiful wildflower displays, and waves of settlements based on livestock grazing and agriculture. This was followed by a succession of dry years that shattered the dreams of the settlers, and wiped out all but the most determined or fortunate individuals.

After World War II the development of new well and irrigation technology made it possible to tap the valley's considerable ground water supplies and extended its agricultural possibilities. Water-hungry crops such as alfalfa and onions are now grown in many parts of the valley, even during dry years. Gold and silver, tungsten, and other mining ventures have been undertaken in many places around the Antelope Valley, and mining - especially for borax - still continues in the Boron area. During and after World War II, Antelope Valley's defense and aerospace industries grew leaps and bounds; today, they dominate the region.