Smoking cannabis remains the most common mode of consumption amongst pregnant people, yet the effects on placentation remain poorly understood. While prior studies have focused on exposure to single components of cannabis (i.e., Δ9-THC and CBD), this approach overlooks the complex toxicology and pharmacology of cannabis smoke exposure (CaSE). In this study, we used an in vitro model of human trophoblast differentiation to investigate the impact of CaSE compared to Δ9-THC. We show that CaSE, but not Δ9-THC induces CYP1A1 expression, a marker of exposure to combustion by-products. CaSE reduced hCG protein levels and ERVW-1gene expression, suggesting impaired syncytialization. Exposure to CaSE (1%, 2.5%) elevated ROS without impacting membrane potential, whereas CaSE (5%, 10%) reduced ATP production, indicating dose-dependent mitochondrial dysfunction. Antioxidant genes, SOD1 and SOD2, were distinctly altered indicating the divergence in oxidative stress responses. Interestingly CB1R antagonism rescued the effects of Δ9-THC exposure, but not CaSE-mediated effects on differentiation markers. Since most cannabis users consume cannabis by smoking, and smoke exposure differs from single components (Δ9-THC). It is critical that preclinical models consider smoking when evaluating the impacts of cannabis use during pregnancy.