Stress and well-being are important life experiences, but we cannot improve well-being by avoiding stress. If we want to increase well-being, we can start by determining the relationship between stress and well-being and other factors that may be effective in this relationship. This cross-sectional study investigates the hypothetical mediating and moderating roles of self-transcendence and coping flexibility in the relationship between stress and mental well-being among Turkish university students. A total of 403 students enrolled in a state university in Türkiye participated in the study. The sample was 75% female ( n = 302) and 25% male ( n = 101), with ages ranging from 18 to 25 years ( M = 21.21, SD = 2.70). Findings revealed that stress significantly predicted university students’ mental well-being in a negative direction. Furthermore, the study identifies self-transcendence and coping flexibility as hypothetical mediators in the relationship between stress and mental well-being. Finally, it was found that coping flexibility moderated the effect of stress on self-transcendence and mental well-being. Under conditions of high coping flexibility, there are stronger, negative associations between stress and self-transcendence and stress and mental well-being. Overall, this study contributes to the understanding of the important role of self-transcendence and coping flexibility in promoting mental well-being and combating stress in the university environment.