Background: Cancer-related fatigue (CRF) often co-occurs with insomnia and both are incapacitating adverse toxicities of cancer and its treatment which may persist months and years after the completion of treatment. Yoga and Cognitive Behavioral Therapy for Insomnia (CBT-I) are promising behavioral approaches for improving CRF and insomnia among cancer survivors. However, the influence of changes in insomnia resulting from participating in yoga or CBT-I on the subsequent changes in CRF is not fully understood. Methods: We conducted mediation analyses on data collected from a multicenter phase III RCT among cancer survivors who were randomized to receive 1) Yoga for Cancer Survivors (YOCAS, 75-min./session, 2x/wk. for 4 wks.), 2) CBT-I (90-min./session, 1x/wk. for 8 wks.), or 3) a behavioral placebo (ASCO recommended Survivorship Education, 75-min/session, 2x/wk. for 4 wks.). Brief Fatigue Inventory and Insomnia Severity Index were used to assess CRF and insomnia, respectively, at pre-, mid-, and post-intervention. Causal mediation analyses were conducted to estimate the influence of changes in insomnia at mid-intervention resulting from participating in YOCAS, CBT-I, or behavioral placebo on subsequent changes in CRF at post-intervention. Results: 550 survivors (93% female; mean age 57 years; 75% were breast cancer survivors) completed baseline and post-intervention assessments. YOCAS, compared to placebo, significantly improved CRF and insomnia at mid-intervention (CRF: -0.38±0.16, p = 0.01; Insomnia: -1.15±0.35, p < 0.01) and post-intervention (CRF: -0.35±0.17, p = 0.03; Insomnia: -1.43±0.41, p < 0.01). Among YOCAS participants, improvement in insomnia at mid-intervention significantly influenced the subsequent reduction in CRF (-0.14±0.06, p = 0.01) and accounted for 37% (95% CI: 0% - 78%) of the total reduction in CRF at post-intervention. CBT-I, compared to placebo, also significantly improved CRF and insomnia at mid- (CRF: -0.32±0.18, p = 0.06; Insomnia: -2.64±0.40, p < 0.01) and post-intervention (CRF: -0.59±0.18, p < 0.01; Insomnia: -4.95±0.46, p < 0.01). Among CBT-I participants, the improvement in insomnia at mid-intervention significantly influenced the subsequent reduction in CRF (-0.40±0.09, p < 0.01) and accounted for 60% (95% CI: 21% - 99%) of the total reduction in CRF at post-intervention. Conclusions: Both YOCAS and CBT-I effectively improve CRF and insomnia among survivors. 37%-60% of the reduction in CRF resulting from participating in YOCAS or CBT-I is due to improvement in insomnia. Clinicians should consider prescribing YOCAS yoga or CBT-I for survivors who experience CRF and insomnia. Clinical trial information: NCT02613364.