Informed and effective management of emerging infectious diseases can be improved by a clear understanding of host–pathogen–environment interactions. Impacts of the seasonal environment on pathogen dynamics and host responses are poorly described in most reptile host–fungal pathogen systems. Here, we describe seasonal patterns of ophidiomycosis, a disease caused by the fungus Ophidiomyces ophidiicola (Oo), in a population of pygmy rattlesnakes, Sistrurus miliarius, in central Florida. We used field observations of gross clinical signs of disease in combination with qPCR on skin swabs to examine the seasonal prevalence of Oo and patterns of clinical presentation in hosts. We monitored thermoregulatory behaviors, ecdysis, and reproductive status in free-living snakes to examine seasonal associations between infection and host coping responses. Both the prevalence of Oo and clinical signs of disease varied strongly with the season (winter high and summer low). In both seasons, the presence of clinical signs was a strong predictor of the presence of Oo as identified by qPCR on skin swabs (78% probability across seasons). Snakes with clinical signs of disease were more likely to be observed exhibiting thermoregulatory behavior or in ecdysis compared to non-clinical snakes across seasons. The prevalence of Oo was not significantly different in pregnant snakes compared to other reproductive categories, but pregnant females were less likely to exhibit clinical signs of disease compared to males. Our results highlight strong seasonal patterns in both host clinical signs and Oo prevalence and support the efficacy of using gross clinical signs of disease in combination with qPCR on skin swabs to assess disease dynamics in free-living snakes. We also identify ecdysis and thermoregulatory behaviors as components of the seasonal disease-coping response and highlight the need to examine these behaviors as potential drivers of seasonal infection outcomes in reptiles afflicted with fungal pathogens.