Background: Nurses are susceptible to several mental problems, such as fear, stress, and depression due to the COVID-19 pandemic, which affects their emotional well-being. However, resilience plays an important role in mitigating the effects of COVID-19. Objective: This study was to examine the mediating role of resilience in the relation between fear, stress, and depression of nurses during COVID-19 health emergencies. Methods: A cross-sectional—predictive study was carried out. The variables analyzed were fear, resilience, stress, and depression. A total of 286 nurses from 2 hospitals in the cities of Juliaca and Puno, Peru. Data analyses were performed using structural equation modeling (SEM). Results: Analyses showed that the variables were significantly related (P <.01). In addition, a confirmatory analysis of the hypothesized model using structural equation modeling shows that fear and stress are predictors of depression, and that resilience plays a role in mediating the effect of fear on stress (X2 = 534.69, gl = 372, P =.000; TLI =.902, CFI =.910, RMSEA =.039 [95% CI = 0.032-0.046], and SRMR =.065). Conclusion: Nurses tend to develop fear, stress, and depression. Resilience reduces the impact of these psychological variables. Hospital management should provide psychological support and training for nurses in coping strategies.