Background: There is a paucity of prospective longitudinal studies examining the associations between maternal use of alcohol and tobacco during pregnancy and the risk of cannabis use in offspring. The aim of this study was to examine the association between prenatal alcohol and tobacco exposures and offspring cannabis use. Methods: Data were from the Raine Study, a longitudinal prospective birth cohort based in Western Australia. Cannabis use at 17 years of age was measured with a self-reported questionnaire developed to capture risky behaviors in adolescents. Associations between prenatal alcohol and tobacco exposures and the risk of cannabis use in offspring were examined using log-binomial regression models, computing relative risk (RR). We also computed the E-values (E) to estimate the extent of unmeasured confounding. Results: After adjusting for potential confounders, we observed increased risks of cannabis use in offspring exposed to first trimester prenatal alcohol use (RR = 1.38, 95% CI: 1.09–1.75; E = 2.10, CI:1.40) and tobacco use (RR = 1.42, 95% CI: 1.08–1.86; E = 2.19, CI:1.37) as well as third trimester prenatal alcohol use (RR = 1.39, 95% CI: 1.09–1.79; E = 2.13, CI:1.40) and tobacco use (RR = 1.39, 95% CI: 1.09–1.79; E = 2.21, CI:1.34]. We also noted dose-response associations in which risk estimates in offspring increased with the level of exposures to prenatal alcohol and tobacco use. Conclusion: These findings provide epidemiological evidence for effects of prenatal alcohol and tobacco exposures on offspring cannabis use. Although these results should be confirmed by other studies, the present study adds to the mounting evidence suggesting that women should be encouraged to abstain from alcohol and tobacco during pregnancy.