IntroductionNeurofibromatosis (NF) is chronic neurogenetic condition that increases risk for poor quality of life, depression, and anxiety. Given the lack of biomedical treatments, we developed the “Relaxation Response Resiliency for NF” (3RP‐NF) program to improve psychosocial outcomes among adults with NF.ObjectiveTo move toward effectiveness testing, we must understand mechanisms that explained treatment effects. We tested whether our hypothesized mechanisms of change—mindfulness, coping, and optimism—mediated improvements in quality of life, depression, and anxiety among adults in the 3RP‐NF program (N = 114; ages 18–70; 72.80% female; 81.58% White).MethodsWe conducted mixed‐effects models to assess whether these mechanisms uniquely mediated outcomes.ResultsImprovements in quality of life were most explained by coping, (b = 0.97, SE = 0.28, CI [0.45, 1.56]), followed by mindfulness (b = 0.46, SE = 0.17, CI [0.15, 0.82]) and optimism (b = 0.39, SE = 0.12, CI [0.17, 0.65]). Improvements in depression and anxiety were most explained by mindfulness (b = −1.52, SE = 0.38, CI [−2.32, −0.85], CSIE = −0.26; b = −1.29, SE = 0.35, CI [−2.04, −0.67], CSIE = −0.23), followed by optimism (b = 0.39, SE = 0.12, CI [0.17, 0.65]; b = −0.49, SE = 0.20, CI [−0.91, −0.13]), but were not explained by coping (b = 0.22, SE = 0.43, CI [−0.62, 1.07]; b = 0.06, SE = 0.46, CI [−0.84, 0.97]), respectively.ConclusionsTargeting mindfulness, coping, and optimism in psychosocial interventions may be a promising way to improve the lives of adults with NF.