Objectives: Although ambiguous and uncertain situations, such as those dealing with the threat of widespread viral illness, may have pronounced psychological ramifications, there have been few studies that examined the factors that contributed to such outcomes. The purpose of the present investigation was to examine emotional reactions to a health threat. Design: A structural equation model examined the interplay between anxiety and intolerance of uncertainty, as sequentially mediated by appraisals and coping strategies. Methods: Adult participants over the age of 18 (N = 1,027) completed online self‐report measures during the H1N1 pandemic in 2009. Results: Greater intolerance of uncertainty was related to lower appraisals of self‐ and other control, which predicted low levels of problem‐focused coping and greater reports of H1N1‐related anxiety. Additionally, individuals with a high intolerance of uncertainty were more likely to perceive the pandemic as threatening and also were more apt to use emotion‐focused coping strategies, and both of these factors predicted elevated levels of anxiety. Conclusions: Together, these data indicate that threats, such as those related to a potential pandemic, not only have implications for physical health, but also for psychological distress, and that such outcomes vary with a constellation of appraisal and coping factors. Statement of contribution: What is already known on this subject? It has been established that the public is often confused by the threat that a potential pandemic virus poses and that they are unsure of what information related to the disease they can trust. Government health agencies often walk the line of minimizing the threat to prevent panic, but simultaneously emphasize the importance of action (vaccination) to prevent a worldwide pandemic. What does this study add? Beyond the physical threat of a pandemic, a significant psychological toll may occur for certain individuals. Anxiety regarding H1N1 is heightened amongst those who cannot tolerate uncertainty. Appraisals of threat, control, and the use of emotion‐focused coping mediate the above relationship.