Cannabidiol, a big non-psychotomimetic compound derived from Cannabis sativa, is a prospective therapeutic agent for a assortment of illnesses such as inflammatory illnesses, chronic neurodegenerative illnesses, and cancers. Right here, we located that the mixture of cannabidiol and TNF-associated apoptosis-inducing ligand (TRAIL) produces synergistic antitumor effects in vitro. Nevertheless, this synergistic impact was not observed in typical colonic cells. The levels of ER pressure-associated proteins, like C/EBP homologous protein (CHOP) and phosphorylated protein kinase RNA-like ER kinase (PERK) have been enhanced in remedy of cannabidiol. Cannabidiol enhanced considerably DR5 expression by ER pressure. Knockdown of DR5 decreased the combined impact of cannabidiol and TRAIL. On top of that, the mixture of TRAIL and cannabidiol decreased tumor development in xenograft models. Our research demonstrate that cannabidiol enhances TRAIL-induced apoptosis by upregulating DR5 and suggests that cannabidiol is a novel agent for escalating sensitivity to TRAIL.