During outbreaks of deadly emerging pathogens (e.g., Ebola, MERS-CoV) and bioterror threats (e.g., smallpox), actively monitoring potentially infected individuals aims to limit disease transmission and morbidity. Guidance issued by CDC on active monitoring was a cornerstone of its response to the West Africa Ebola outbreak. There are limited data on how to balance the costs and performance of this important public health activity. We present a framework that estimates the risks and costs of specific durations of active monitoring for pathogens of significant public health concern. We analyze data from New York City’s Ebola active monitoring program over a 16-month period in 2014–2016. For monitored individuals, we identified unique durations of active monitoring that minimize expected costs for those at “low (but not zero) risk” and “some or high risk”: 21 and 31 days, respectively. Extending our analysis to smallpox and MERS-CoV, we found that the optimal length of active monitoring relative to the median incubation period was reduced compared to Ebola due to less variable incubation periods. Active monitoring can save lives but is expensive. Resources can be most effectively allocated by using exposure-risk categories to modify the duration or intensity of active monitoring.