Pathways from maternal tobacco, marijuana, stress, and anger in pregnancy to infant reactivity and regulation (RR) at 9 months of infant age were examined in a low‐income, diverse sample beginning in the first trimester of pregnancy, with fetal growth and postnatal stress/anger as potential mediators, and infant sex as a moderator. Participants were 247 dyads (173 substance‐exposed infants). There were no direct effects of prenatal risk on RR and no moderation by sex. However, there were significant indirect effects on RR via poor fetal growth and higher postnatal anger. The study adds to the sparse literature on joint effects of tobacco and marijuana, and highlights the role of fetal growth and maternal anger as important pathways from prenatal risk to infant RR.