In the current study, we investigated the relationships among academic stress, psychological capital (PsyCap), and well-being and the effect of the demographic variables of gender, majors, and academic years on academic stress and PsyCap. We used the structural equation model to investigate the mediating role of PsyCap between academic stress and well-being. The participants (N = 827) included students from a midsized university in the Eastern Province of Saudi Arabia (636 females, 191 males) who comprised 450 science and 377 humanities majors from all academic years. To collect data, we utilized the Academic Stress Inventory, the Psychological Capital Questionnaire, and the Warwick-Edinburgh Mental Well-Being Questionnaire. The structural equation model analysis results revealed that PsyCap was a full mediator between academic stress and wellbeing. Gender did not affect on PsyCap or academic stress. In addition, the academic majors affected PsyCap: Students in the humanities majors had better PsyCap than those in the science majors. Furthermore, the academic years affected academic stress; specifically, academic stress decreased as students progressed through their academic years. Therefore, science majors in their first academic year were the most in need of a PsyCap-based intervention.