Mission Bay Park is home to many rare and endangered plant, animal and bird species. Endangered bird species of Mission Bay include the California least tern and the Light-footed Ridgeway’s Rail. The California Least Tern is a federally-listed endangered subspecies, and the death of a least tern chick severely reduces chances for the bird's survival. The roaming of predators on site prevents adult least terns from nesting. The Least Terns migrate to Mission Bay to nest from April to September every year. Buffer areas near the nesting sites at Stony Point, North Fiesta Island and Mariner’s Point are closed to the public during nesting season (April 15 to September 15). The Light-footed Ridgeway’s rail is a year-round resident in our marshes and wetlands. Their nesting activity is from mid-March through August.

In a multi-agency effort, that includes the City of San Diego Park and Recreation Department, the U.S. Department of Fish and Wildlife Service, the California Department of Fish and Wildlife, and the Wildlife Services Program of the U.S. Department of Agriculture; professionals from the wildlife program carry out the humane trapping of least tern predators who come to least tern nesting sites. This includes skunks, opossums, and feral cats and dogs, believed to be former pets who were abandoned by their owners. Sites are located on North Fiesta Island, Mariner's Point, Stoney Point, and a small island called "Government Island" used by the Federal Aviation Agency.

Anyone exercising a dog in Mission Bay Park should adhere to the posted leash laws, and should consider leashing the dog in off-leash areas as well during the least tern season.

Other birds that can be seen in Mission Bay Park are the great blue heron, the osprey, mallards, avocets, black-necked stilts and the Belding's savannah sparrow.