In this cross-sectional study, we analyzed the relationship between resilience, cardiorespiratory fitness, and mental health-related quality of life, and examined whether resilience acts as a mediator between the latter two. The study included 770 university students, aged 18-30 years, from Cuenca, Spain. Anthropometric, sociodemographic, cardiorespiratory fitness (20 m shuttle run test), biochemical parameters, resilience, and mental health-related quality of life measurements were analyzed. The results showed that mental health-related quality-of-life values were significantly higher in students who had good cardiorespiratory fitness and a high level of resilience. Moreover, resilience acted as a partial mediator between cardiorespiratory fitness and mental health-related quality of life at 33.79%. Therefore, in young adults, resilience mediates the relationship between cardiorespiratory fitness and mental health-related quality of life. These findings should be taken into account by nurses and other public health professionals, because in addition to the development of physical activity interventions to improve mental health-related quality of life, it is necessary to implement measures that increase resilience to achieve mental wellness.