They extend for approximately 61 miles (98 km) southeast of the Los Angeles Basin largely along the border between Orange and Riverside counties.

From the foot of the escarpment, the mountains and canyons of De Luz, Sandia Creek and others below it, run to the south to the Santa Margarita River.

The northern side of the range is defined by the Santa Ana River, which heads about 50 miles (80 km) further east, in the San Bernardino Mountains.

Santiago Creek drains much of the northern part of the range and empties into the Santa Ana River near downtown Orange.

Irvine Lake, the largest body of fresh water in Orange County, is in the northwest part of the range near Villa Park.

[5] At the time of Portola's visit, the Santa Anas were settled by three main groups of indigenous peoples, the Tongva in the north, the Acjachemen in the west and Payomkowishum in the east and south.

[9] As part of the California Floristic Province, the Santa Ana Mountains host a diverse array of plant species within distinctive natural (plant) communities, including coastal sage scrub, chaparral, riparian woodland, southern oak woodland, rocky outcrop, vernal pool, valley grassland, and closed-cone montane coniferous forest.

Fragrant sages, broadleaf evergreen shrubs and trees, perennial bunchgrasses, succulents (Dudleya species), and fire-following flowers grow in the rugged terrain.

A surprising variety of wildlife species can be found, including mountain lion,[10] mule deer, bobcat, coyote, gray fox, American badger, ring-tailed cat, spotted skunk, western gray squirrel, long-tailed weasel, dusky-footed woodrat, kangaroo rat, bats, spotted owl, western pond turtle, steelhead, coast horned lizard, least Bell's vireo, golden eagle, mountain quail, canyon wren, speckled rattlesnake, Pacific rattlesnake, common kingsnake, gopher snake, western fence lizard, arroyo toad, western spadefoot toad, California tree frog, California sister butterfly, various Aphonopelma species of tarantula, and many more.

Commercial resources collected since the 1870s have included metals such as lead, silver, tin, and zinc, and minerals such as clay, coal, gypsum, and limestone.

[12] The mountains form a natural barrier between the Inland Empire region to the east and the job centers of Orange County to the west.

Because of this, several proposals have been floated to excavate a highway tunnel through the Santa Ana Mountains, although the multibillion-dollar idea has drawn criticism from environmentalists and others concerned about cost and safety in the earthquake-prone region.