Rabbit hemorrhagic disease virus serotype 2 (RHDV2), the cause of a highly contagious and fatal lagomorph disease, rapidly spread through the western United States and Mexico. In response, an ad hoc interagency/zoo/academia/non-profit team implemented emergency conservation actions to protect California’s Central Valley endemic, endangered riparian brush rabbit (Sylvilagus bachmani riparius, RBR) from RHDV2. RBRs have lost over 90% of historic habitat, and remnant habitat is fragmented and prone to flooding and wildfire. The team first implemented a vaccine safety trial by administering Filavac VHD K C+V® vaccine (Filavie, France) to 19 wild RBRs captured and temporarily held in captivity. Rabbits were monitored for adverse effects and serum collected prior to, and at 7-10-, 14-20-, and 60-days post-vaccination for antibody response determination. No adverse vaccine effects were documented; therefore a large-scale effort to reduce extinction risk by vaccinating ~15% of the estimated wild population began in September 2020. Population estimation via remote camera transects coupled with predictive modeling informed vaccination goals. To date, 674 RBRs have been vaccinated at least once. In Spring 2022, RHDV2 deaths were confirmed in unvaccinated RBRs and sympatric desert cottontails (Sylvilagus audubonii). Vaccination, disease surveillance and population monitoring are continuing to detect possible disease-related population change.