Cannabis has been used throughout history for medicinal and recreational purposes. The most notable cannabinoids derived from these plants are cannabidiol (CBD) and tetrahydrocannabinol (THC). Although well studied for their therapeutic effects, and highly debated concerning their recreational use, the underlying mechanisms of their biological effects are poorly defined. Here we used isobaric tag-based sample multiplexed proteome profiling to investigate protein abundance differences in the human neuroblastoma SH-SY5Y cell line treated with CBD and THC. We highlighted significantly regulated proteins by each treatment and performed pathway classification and associated protein-protein interaction analysis. Our data suggest that these treatments may result in mitochondrial dysfunction and induce endoplasmic reticulum stress. This dataset can be mined further to investigate the potential role of CBD and THC in various biological and disease contexts and thus provide a foundation for future studies.