Maternal depression has been linked to increased risk of substance use disorders (SUDs) in offspring. Cross-sectional studies have identified relationships among maternal depression, externalizing disorders and SUDs, but no longitudinal examination of causality has been undertaken. In order to address this gap in the literature, depression and externalizing disorders at or prior to age 15 were tested as mediators of the relationship between maternal depression and SUDs diagnosed between ages 16 and 20 in a sample of 702 Australian youth (363 women) using path models. Mothers' and fathers' substance diagnoses and earlier onset of substance abuse in youth were controlled for in all analyses. Consistent with previous work, maternal depression predicted SUDs between ages 16 and 20. An indirect effect of maternal depression through youth externalizing disorders diagnosed by age 16 was detected for alcohol and cannabis use disorders, but not drug disorders. Early adolescent depression was not a mediator of the relationship between maternal depression and any of the substance outcomes measured. To our knowledge, this study is the first to examine depression and externalizing disorders in early adolescence as mediators of the effect of maternal depression on psychopathology in later adolescence. Further work is needed to understand how family environment and genetic factors may explain the mediation by externalizing disorders.