Darker skin color is associated with discrimination and unfair treatment and may contribute to persisting health disparities. This study examined whether darker skin color was associated with smoking cessation and whether this association was moderated by sex and race. This study also explored whether biological and psychosocial factors, including nicotine and cotinine concentrations, discrimination, distrust, and neuroticism, mediated this association. The data for this study came from a prospective smoking cessation intervention that included 224 Black and 225 White adults from Kansas City, Missouri. Skin color was assessed using a DermaSpectrometer to measure melanin contained within the skin. Point prevalence smoking abstinence was biochemically-verified and assessed at weeks 4 and 26. Hierarchical logistic regression analyses were conducted to evaluate hypothesized relations between skin color and smoking cessation. Interactions between race and sex with skin color were also evaluated. While skin color was not associated with smoking cessation in the overall sample or among Blacks only, results indicated that sex moderated the effect of skin color on smoking cessation after adjusting for race and other covariates. Among males, darker skin color was associated with lower odds of achieving smoking abstinence at weeks 4 (OR = 0.60 [95% CI = 0.36, 0.99]) and 26 (OR = 0.52 [95% CI = 0.29, 0.91]). Skin color did not predict smoking cessation among females. Skin color was positively correlated with discrimination (r = 0.15, p = 0.02), cynicism/distrust (r = 0.14, p = 0.03) and neuroticism (r = 0.24, p < 0.01) among males only. However, these factors did not mediate the association between skin color and smoking cessation. Skin color may contribute to cessation-related health disparities among Black males, but more research is needed to understand the psychosocial and biological mechanisms through which skin color influences tobacco cessation.