This study aimed to identify biopsychosocial factors associated with fatigue, physical activity, and perceived benefits of and barriers to exercise in adults with inflammatory bowel disease and to compare them with those with fibromyalgia and healthy controls. A cross-sectional online survey was conducted. Hierarchical linear regressions were used to examine correlates of fatigue and physical activity. Analysis of variance and Kruskal–Wallis tests were used to compare levels of fatigue and physical activity between the groups. Overall, 387 participants completed the study (inflammatory bowel disease: n = 232; fibromyalgia: n = 102; healthy controls: n = 53). Significant correlates of fatigue included pain catastrophizing (p = .006), sleep quality (p = .003), and depressive symptoms (p < .001). Perceived barriers to exercise were associated with depressive symptoms (p = .003). Correlates of perceived benefits of exercise included anxiety (p = .036), depressive symptoms (p = .014), coping (positive reframing) (p = .018), and social support (from family) (p = .033). The fibromyalgia group had the greatest fatigue interference and the lowest score for physical activity, followed by the inflammatory bowel disease group and healthy controls (p < .05). Given the interplay between depressive symptoms, fatigue, and benefits/barriers to exercise, there is a need for more psychological interventions to be developed and tested in order to reduce fatigue and increase physical activity to better manage disease-related outcomes.