The current study investigated whether mindfulness and psychological flexibility uniquely and separately accounted for variability in psychological distress (somatization, depression, anxiety, and general psychological distress). An ethnically diverse, non-clinical sample of college undergraduates (N = 494, 76% female) completed a web-based survey that included the self-report measures of interest. Consistent with prior research, psychological flexibility and mindfulness were positively associated with each other, and tested separately, both variables were negatively associated with somatization, depression, anxiety, and general psychological distress. Results also revealed that psychological flexibility and mindfulness accounted for unique variance in all four measures of distress. These findings suggest that mindfulness and psychological flexibility are interrelated but not redundant constructs, and that both constructs are important for understanding the onset and maintenance of somatization, depression, anxiety, and general distress.