Objectives (1) To explore moderators of the effects of home-based exercise on reductions in physical and mental fatigue scores in postpartum depressed women and (2) to explore mediators of the intervention on changes in physical fatigue. Method Eighty-eight women in the postpartum period (4–38 weeks) obtaining a score ≥10 on the Edinburgh Postnatal Depression Scale were randomly assigned to a 12-week individualized home-based exercise intervention (n=46) or a no-treatment control group (n=42). The present analyses include the 35 women who adhered to the intervention and the no-treatment control group. Participants completed a cardiovascular fitness test, and a battery of questionnaires assessing the outcomes (Physical and Mental Fatigue) as well as potential moderators and mediators at baseline and posttreatment. Results Hierarchical linear regressions evaluating moderators of changes in mental fatigue with exercise showed that the intervention was effective for women entering the study later in the postpartum period (P=.001) and women with higher depression scores (P=.014). Reductions in physical fatigue with exercise were partially mediated by reductions in perceived stress and increased exercise-related energy expenditure. Conclusion Identification of moderators allows for the tailoring of exercise interventions to particular subgroups of women that are most likely to benefit. The identified mediators may be enhanced and directly tested in future trials.