The COVID-19 vaccine development, testing, and approval processes have moved forward with unprecedented speed in 2020. Although several vaccine candidates have shown promising results in clinical trials, resulting in expedited approval for public use from the U.S. Food and Drug Administration, recent polls suggest that Americans strongly distrust the vaccine and its approval process. This mistrust stems from both the unusual speed of vaccine development and reports about side effects. This article applies insights from behavioral economics to consider how the general public may make decisions around whether or not to receive a future COVID-19 vaccine in a context of frequent side effects and preexisting mistrust. Three common cognitive biases shown to influence human decision-making under a behavioral economics framework are considered: confirmation bias, negativity bias, and optimism bias. Applying a behavioral economics framework to COVID-19 vaccine decision-making can elucidate potential barriers to vaccine uptake and points of intervention for clinicians and public health professionals.