Along its lower 10 miles (16 km) the river forms a large floodplain as it crosses Camp Pendleton Marine Corps Base.

Draining 1,922 square kilometres (742 sq mi), the Santa Margarita Watershed is the second largest river basin on the Southern California coastal plain.

[15] Approximately 4,334 acres (1,754 ha) of the middle course of the Santa Margarita River in Temecula Canyon are managed by San Diego State University as the Santa Margarita Ecological Reserve, a collaboration of the Bureau of Land Management, California Department of Fish and Wildlife and The Nature Conservancy.

Major fishes in the Santa Margarita River include the rainbow trout (Oncorhynchus mykiss), arroyo chub (Gila orcuttii), California killifish (Fundulus parvipinnis), striped mullet, longjaw mudsucker, staghorn sculpin.

The successful recolonization has been attributed to a rebuilt weir and new fishway at Camp Pendleton which allowed the lamprey to find passage into the river.

[16] Aquatic and semi-aquatic mammals include California golden beaver (Castor canadensis subauratus), muskrat, raccoon and long-tailed weasel.

[18] Major riparian plants include arroyo, black, narrowleaf, Pacific, and red willow (Salix spp); California sycamore (Platanus racemosa), Fremont cottonwood (Populus fremontii), mulefat (Baccharis salicifolia) and White alder (Alnus rhombifolia).