Abstract Rabbit hemorrhagic disease virus 2 (RHDV2), recently detected in the western United States, has the potential to cause mass mortality events in wild rabbit and hare populations. Currently, few management strategies exist other than vaccination. We developed a spatially explicit model of RHDV2 for a population of riparian brush rabbits ( Sylvilagus bachmani riparius ), a subspecies of brush rabbit classified as endangered in the United States, on a subsection of the San Joaquin River National Wildlife Refuge. The goal of our model was to provide guidance regarding vaccination strategies for an endangered rabbit species. Our model predicts that increased interactions between rabbits (a proxy for landscape connectivity) and disease transmission rates among susceptible hosts (individual brush rabbits and conspecifics) have the greatest influence on the outcome of a potential vaccination campaign. Our model projects that across a range of parameter estimates (given an RHDV2 incursion), the median estimated population size with a 0%–10% vaccination rate after 1 year is 538 rabbits (95% Confidence Interval [C.I.] 69–1235), approximately 36% of the expected size of the study population of 1470 rabbits without an RHDV2 introduction. With a 10%–20%, 20%–30%, or 30%–40% vaccination rate, the median estimated population size increased to 628 rabbits (95% C.I. 130–1298), 723 rabbits (95% C.I. 198–1317), and 774 rabbits (95% C.I. 228–1410), respectively. These estimates represent 43%, 49%, and 53% of the expected population size without an RHDV2 introduction. Overall, a 1% increase in vaccination rate was associated with a six rabbit (95% C.I. 5–7) increase in total remaining population size. This result is dependent on assumptions regarding environmental transmission, home range size (and contact rates of rabbits). Given the relatively short lifespan of rabbits and the potential need for boosters, vaccination programs are most likely to be successful for small target populations where relatively high vaccination rates can be maintained.