Owing to their omnivorous diet, den-site habits, foraging activities, mating behaviors, and other pertinent habitat-use and natural-history traits, Spilogale putorius (Eastern Spotted Skunk [ESS]) are exposed to a wide variety of pathogenic agents. Understanding the diversity of infectious diseases affecting ESS in conjunction with the role this species plays in the disease ecology of these pathogens is crucial not only for devising efficacious management strategies, but also in formulating comprehensive veterinary and public health strategies for combatting zoonotic diseases associated with this species. Herein I review the reported infectious diseases of ESS. I address the implications of these pathogens for current and future population health of the species with reference to the changing dynamics of ESS disease ecology, influenced by increasing habitat fragmentation, exposure to pathogens across the domestic–wildlife interface, fluctuating climatic patterns, antimicrobial-resistant pathogens, and the profusion of immunosuppressant chemicals throughout the environment. Employing a One Health framework to evaluate the role that ESS play in the disease ecology of zoonoses further highlights the interrelationships of ESS health to the health of humans, domestic animals, and other wildlife. The potential for ESS to serve as hosts, “dilutors”, and/or sentinels for zoonoses underscores their importance in public health and provides an opportunity to leverage their potential disease-mitigating attributes for the conservation of ESS aligned with their provision of ecosystem services.