Psychological well-being and distress are critical components of college adjustment that are intricately entwined with student retention and success during and after college. This 5-wave longitudinal study used growth mixture modeling to explore heterogeneous trajectories of psychological well-being (self-esteem) and distress (depression, anxiety, stress) spanning just before college to the end of the fourth year. Students (N = 5,537) most commonly were best characterized by trajectories of stable positive or moderate adjustment, though some were better characterized by trajectories of low or variable adjustment. These latter subgroups may represent the highest-need students, for whom identifying pre-college risk and protective factors is crucial. Some notable differences emerged in trajectories for women versus men. Further, several individual characteristics at the cusp of college predicted these four-year trajectories. The strongest psychological functioning predictors were self-esteem, distress, and stress (less consistently, resilience and self-efficacy). The most predictive cognitive-affective strategy was avoidant emotional coping, followed by cognitive reappraisal and expressive suppression (less consistently, problem-focused and active emotional coping). Social well-being factors that best differentiated adjustment trajectories were general social support, followed by support from family and then from friends. These findings have implications for targeting at-risk students upon university arrival to promote optimal long-term adjustment.