People have influenced Earth’s biodiversity for millennia, including numerous introductions of domestic and wild species to islands. Here, we explore the origins and ecology of the Santa Catalina Island ground squirrel (SCIGS;
Otospermophilus beecheyi nesioticus
), one of only five endemic terrestrial mammals found on California’s Santa Catalina Island. We synthesized all records of archaeological/palaeontological SCIGS, conducted radiocarbon dating and stable isotope analysis of the potentially earliest SCIGS remains and performed genetic analysis of modern SCIGS. Squirrels were not identified in island palaeontological deposits, but at least 12 island archaeological sites contain SCIGS bones, including some that are butchered or burned. All directly dated SCIGS bones are Late Holocene in age and younger than approximately 1290 cal BP. The first mitochondrial genome for modern
Otospermophilus beecheyi
and 15 modern SCIGS mitogenomes document at least one introduction of squirrels. Stable isotope data indicate variable SCIGS diets and potential subsidies from marine environments to terrestrial plants consumed by some individuals. We cannot rule out a natural overwater dispersal, but the earliest SCIGS remains post-date the earliest evidence for people by several millennia and, along with other lines of evidence, support a human-assisted translocation of squirrels during the Late Holocene. These data illustrate the important role of Indigenous people in shaping and enhancing island biodiversity and ecology around the world.