Background: The study of health-related quality of life (HRQOL) is an important topic in mental health around the globe. However, there is the need for more evidence about the cumulative influence of psychological variables on HRQOL. The main aim of the study was to evaluate how specific personality traits might explain scores in HRQOL and to explore how this relationship might be mediated by coping styles and psychological distress. Methods: Young Colombian subjects (N = 274) were included (mean age: 21.3; SD = 3.8). The Short-Form Health Survey was used to measure HRQOL. For assessment of psychological variables, the Hospital Anxiety and Depression Scale, the Zung Self-Rating Anxiety Scale, The Coping Inventory for Stressful Situations and the short version of Big Five Inventory were used. Results: The personality trait that was the best predictor of HRQOL was openness to experience, forming an explanatory model for HRQOL, along with emotional coping style and depressive and anxious symptoms. Emotional coping style and psychological distress were significant mediators of the relationship between openness and HRQOL. Conclusions: Our findings provide additional data about the cumulative influence of specific psychological variables on HRQOL, in a mostly young female Latin American sample.