Though oxaliplatin is an efficient chemotherapeutic drug for colorectal most cancers (CRC) therapy, sufferers usually develop resistance to it. Due to this fact, a brand new technique for CRC therapy is required. The aim of this examine was to find out the impact of cannabidiol (CBD), one of many parts of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells. We established oxaliplatin-resistant cell traces, DLD-1 R and colo205 R, in CRC DLD-1 and colo205 cells. Autophagic cell demise was induced when oxaliplatin-resistant cells had been handled with each oxaliplatin and CBD. Moreover, phosphorylation of nitric oxide synthase 3 (NOS3) was elevated in oxaliplatin-resistant cells in comparison with that in mother or father cells. Mixed therapy with oxaliplatin and CBD diminished phospho-NOS3 ranges and nitric oxide (NO) manufacturing and resulted within the manufacturing of reactive oxygen species (ROS) by lowering the degrees of superoxide dismutase 2, an antioxidant current within the mitochondria, inflicting mitochondrial dysfunction. Taken collectively, these outcomes recommend that elevated phosphorylation of NOS3 is important for oxaliplatin resistance. The mixture of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS via mitochondrial dysfunction, thus overcoming oxaliplatin resistance.