Squirrels and mice play a vital role in the ecosystem as prey animals for numerous predators. The population of these predators often fluctuates in relation to the abundance of squirrels and mice. There is a wide range of predators that opportunistically prey on squirrels, including hawks, owls, eagles, magpies, ravens, shrikes, skunks, weasels, martens, minks, badgers, wolverines, foxes, coyotes, wolves, bobcats, lynxes, cougars, black-footed ferrets, black and grizzly bears, domesticated cats and dogs, snakes, possums, and even humans. This list is not exhaustive, as there are likely many other predators that target squirrels given the opportunity.

The significance of squirrels as prey animals is complex, but when the population of squirrels declines in a particular area, it can have a cascading effect on the predator population in that same area. For example, certain predators, like members of the weasel family, are specially adapted to pursue ground squirrels into their burrows. Badgers have the ability to dig out squirrel burrows in order to access the squirrels inside.

An illustrative case is the plight of black-footed ferrets, which faced near extinction due to the widespread eradication of prairie dogs, a species of squirrel. Prairie dogs were the primary food source for black-footed ferrets, and when their populations were decimated, the ferrets lost their main source of sustenance, leading to their decline. Thanks to conservation efforts and the recognition of the interdependence between black-footed ferrets and prairie dogs, the ferret population is now recovering as measures were implemented to increase the number of prairie dogs.

It is important to note that the extermination of prairie dogs likely had far-reaching consequences for numerous other predators that relied on them as a food source. The black-footed ferrets simply exemplified the critical link between the squirrels and their own survival.