Predator-prey interactions can be influenced by myriad environmental factors, with moonlight sometimes being a strong driver of nocturnal predator and prey behavior. Lunar illumination can vary based on moon phase, how close the moon is to Earth, and the moon’s position in the sky. On San Clemente Island, the southernmost of the California Channel Islands, there are few nocturnal predator species, and only two mouse species. We investigated the effects of lunar illumination on two native species – the San Clemente Island fox (Urocyon littoralis clementae) and the San Clemente deer mouse (Peromyscus maniculatus) – and two introduced species, the house mouse (Mus musculus) and feral cats (Felis catus) – using generalized additive models. High lunar illumination decreased the nightly activity of house mice (p < 0.07) based on capture success, however deer mice were more active during periods of moderate and high lunar intensity (p < 0.001). Foxes decreased activity after a minimum lunar intensity was met (p < 0.02), and cats exhibited a moderate but significant negative relationship with mean nightly lunar intensity (p < 0.001). This study provides new insight into how lunar illumination may mediate behavioral interactions among endemic and invasive species within a sensitive ecosystem.