1) Multi-species wildlife monitoring across large geographical regions is important for effective conservation planning in response to expected impacts from climate change and land use. Unlike many species of birds, mammals, and amphibians which can be efficiently sampled using automated sensors including cameras and sound recorders, reptiles are often much more challenging to detect, in part because of their typically cryptic behavior and generally small body sizes. Although many lizard species are more active during the day which makes them easier to detect using visual encounter surveys, they may be unavailable for sampling during certain periods of the day or year due to their sensitivity to temperature. 2) In recognition of these sampling challenges, we demonstrate application of a recent innovation in distance sampling that adjusts for temporary emigration between repeat survey visits. We used transect surveys to survey lizards at 229 sites throughout the Mojave Desert in California, USA, 2016. 3) We estimated a total population size of 80 million (90% CI: 64–97 million) for the three most common species of lizards across this 66,830 km2 ecoregion. We mapped how density at the 1-km2 scale was predicted to vary with vegetation cover and human development. We validated these results against independent surveys from the southern portion of our study area. 4) Our methods and results demonstrate how multi-species monitoring programs spanning arid ecoregions can better incorporate information about reptiles.