Considerable evidence supports yoga as a treatment for chronic low-back pain (CLBP), yet more research is needed on the mechanisms of yoga. Yoga may be particularly helpful for military veteran populations, where there is a high prevalence of CLBP due to intensive training requirements. Our objective was to examine possible mechanisms by which yoga reduced disability in a clinical trial of yoga for veterans with CLBP. Using data from a prior randomized controlled trial, we used mediation analysis to examine factors that may mediate or influence the effects of yoga on disability over time. The 12-week yoga intervention study measured outcomes at baseline, 6 weeks, 12 weeks, and 6 months. Fatigue and pain were the variables that met all statistical criteria for mediation of the effect of yoga on disability. The total effect of yoga on disability was significant (β = –2.28; 95% CI –3.93 to –0.64), and this consisted of a direct effect of yoga (β = −1.40; 95% CI −3.02 to 0.25) and a statistically significant indirect effect (β = −0.88, 95% CI −1.91 to −0.15) that was mediated by pain and fatigue. The indirect effect accounted for 38% of yoga’s effect on back-pain disability. Fatigue and pain were not significant as individual mediators. The other mediators—self-efficacy, spinal range of motion, grip strength, core strength, and balance—did not meet published criteria for mediation. Our results suggest that in veterans with CLBP, yoga may reduce pain and fatigue and contribute to reductions in disability. Although pain may be an expected precursor of disability, the finding that fatigue mediates the relationship between a mind-body intervention like yoga and disability appears novel. Fatigue should be measured more widely in yoga research and considered when designing interventions for specific populations such as military veterans with chronic pain.