Significance The decline and progressive fragmentation of many threatened populations increase extinction vulnerability due to outbreaks of infectious disease. Vaccination is one of the few tools available to mitigate these threats, but its use is often hampered by insufficient epidemiological understanding and historic controversies over endangered wildlife vaccination. Using the example of Amur tigers and CDV, we describe a holistic approach to select appropriate disease mitigation strategies based on key epidemiological evidence from the field. We then assess the protection of vaccinated tigers against the locally circulating CDV strain and use modeling to compare the efficacy and cost of potential vaccination programs. This practical approach provides conservation managers with an evidence-based rationale to address disease-mediated extinction risks for threatened wildlife populations.