In response to the COVID-19 pandemic, governments and health authorities worldwide have both recommended and mandated various health-protective behaviors to contain the spread of the virus and ultimately save lives. Despite strong public support for these measures overall, several countries have over the course of the pandemic witnessed a gradual decrease in adherence to recommended health-protective behaviors—a trend that has been attributed to the dawn and rise of pandemic fatigue. In absence of a clear conceptualization and psychometrically validated measure of pandemic fatigue, however, this claim remains highly speculative as the observed decrease in public adherence might very well be driven by a myriad of different factors in- or excluding pandemic fatigue. Tackling this issue and relying on quota-representative repeated cross-sectional and panel data from Denmark and Germany (overall N = 34,582), after introducing a theoretically informed conceptualization of pandemic fatigue and a corresponding brief measure with good psychometric properties, we investigate the development of pandemic fatigue over time, explore who experiences it, identify related emotions and perceptions, and shed light on the link between pandemic fatigue and adherence to various health-protective behaviors. In addition, we explore the causal impact of pandemic fatigue on people’s intention to adhere to different health- protective behaviors in a preregistered online experiment conducted with U.S. participants (N = 1,584). Taken together, our results provide much needed evidence with regard to the existence, nature, correlates, and consequences of pandemic fatigue, informative now as well as for future pandemics.