Background: Recently, workers employed in vaccination points around the world have been subjected to very high workloads to counter the progress of the COVID-19 epidemic. This workload has a negative effect on their well-being. Environmental psychology studies have shown how the physical characteristics of the workplace environment can influence employees’ well-being. Furthermore, studies in the psychology of art show how art can improve the health of individuals. Objectives: The aim of this research was to test a moderated mediation model to verify how appreciation of workplace aesthetics can impact the level of exhaustion of staff working in a vaccination center, the mediating role of positive and negative affects, and the moderating role of interest in art. Methods: Data were collected from a sample of 274 workers (physicians, nurses, reception, and administrative staff) working in the same vaccination center in Italy. Participants answered a self-report questionnaire during a rest break. We used a cross-sectional design. Results: The results show that appreciation of workplace aesthetics impacts employees’ level of exhaustion. This relationship is mediated by positive and negative affects, and interest in art moderates the relationship between positive affects and exhaustion. Conclusions: These findings indicate the central role of workplace aesthetics in influencing healthcare workers’ well-being, and how interest in art can reduce exhaustion levels. Practical implications of the results are discussed.