Background: Black men who have sex with men (BMSM) remain at highest risk for HIV in the United States. Internalized HIV stigma and depression contribute to substance use and condomless anal intercourse (CAI). Religion and spirituality (R/S) are associated with decreased HIV-related risk behaviors for some groups, but their impact among BMSM is uncertain. We investigated the main and moderating roles of R/S on pathways from internalized HIV stigma to CAI while under the influence of drugs. Methods: We used baseline data from 1511 BMSM from the HIV Prevention Trials Network (HPTN) 061 study to examine the associations between internalized HIV stigma, depressive symptoms, alcohol use, and CAI while under the influence of drugs, adjusting for covariates in generalized structural equation models. We then tested whether R/S moderated the association between (1) internalized HIV stigma and depressive symptoms, (2) depressive symptoms and alcohol use, and (3) alcohol use and CAI while under the influence of drugs. Results: Spiritual beliefs [F(1,2) = 9.99, P < 0.001], spiritual activities [F(1,2) = 9.99, P < 0.001], and religious attendance [F(1,2) = 9.99, P < 0.001] moderated the pathway between internalized HIV stigma and depressive symptoms. As internalized HIV stigma increased, those with lower spiritual activity scores experienced significantly higher increases in depressive symptoms compared with those with higher spiritual activity scores whose depressive symptom scores remained unchanged [stigma × spiritual activities B = -0.18 (SE = 0.07), P < 0.001]. Conclusions: Religion and spirituality were protective against CAI among BMSM. Future intervention research should explore ways to incorporate religious and/or spiritual activities to reduce internalized HIV stigma as one way to reduce depressive symptoms among BMSM.