Mesopredators in western North America are facing major changes to their ecosystems, including drought and the expansion of human disturbance. To balance resource needs and risk‐taking on the landscape, mesopredators are likely to shift their habitat use and interspecies interactions. As part of a large‐scale study to help evaluate responses of terrestrial wildlife to severe drought, the California Department of Fish and Wildlife surveyed mesopredator presence across 585 sites in the Mojave Desert (MD) and Central Valley (CV) ecoregions of California. This study spanned a drought year (2016) and a post‐drought year (2017), providing the opportunity to investigate how drought and interspecific interactions may mediate spatial patterns of mesopredator occurrence across a continuum of human disturbance levels. We used single‐season, single‐species, and conditional two‐species occupancy models to elucidate these relationships in both ecoregions. We examined the occupancy and detection of coyotes (Canis latrans) and smaller mesopredators, including bobcats (Lynx rufus) in both ecoregions, raccoons (Procyon lotor) in the CV, and desert kit foxes in the MD (Vulpes macrotis arsipus). The presence of coyotes influenced the detection probability of all other mesopredator species, and the influence of drought varied by species and ecoregion. Detection of mesopredators in the CV was typically higher in 2016, especially at low disturbance sites, suggesting species may have become more active during the drought to meet resource needs. However, detection of mesopredators in the MD tended to increase after the drought, suggesting a response to an increase in resources (e.g., prey). Coyotes in the MD became more detectable in high human disturbance in 2016 and less detectable in 2017, possibly increasing activity during the drought in human‐disturbed areas to obtain anthropogenic resources. Drought not only affects individual species and their relationships to human disturbance, but it can also influence their interspecies interactions and use of different landscape features.