Prenatal exposure to cannabis and tobacco can significantly disrupt critical stages of fetal development, resulting in long-lasting consequences for offspring’s health. Prenatal THC exposure has been shown to impair offspring neurodevelopment, alter metabolic and cardiovascular function, and disrupt reproductive health, with sex-specific effects that persist into adulthood. Similarly, nicotine exposure during pregnancy is associated with structural and functional deficits in the offspring’s pulmonary, neurological, behavioral, cardiac, and renal systems. Epigenetic modifications are a key mechanism through which both THC and nicotine exert their developmental effects, including widespread changes in DNA methylation that influence gene expression and may mediate long-term health outcomes. The rapidly changing landscape of prenatal cannabis and nicotine use, including rising rates of co-use and novel product formulations, highlights the need for ongoing, mechanistic research. Further studies are required to define how these substances impact fetal development and identify shared and distinct molecular pathways, particularly in the context of polysubstance exposure and contemporary delivery methods. Animal models are pivotal in dissecting these pathways and evaluating the direct effects of exposure, free from confounding variables common in human studies. Importantly, they provide a platform to examine both the individual and synergistic effects of THC and nicotine, as well as to uncover underlying mechanisms that may inform intervention strategies and guide public health policy.