Natural bicyclic sesquiterpenes, β‐caryophyllene (BCP) and β‐caryophyllene oxide (BCPO), are present in a large number of plants worldwide. Both BCP and BCPO possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells. BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2 ), but not cannabinoid receptor type 1 (CB1 ). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery. It is known that BCPO alters several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties. Either as a pure substance or a component of plant essential oils, BCPO was found to exhibit antiinflammatory, antioxidant, antiviral, anticarcinogenic, and analgesic properties. β-caryophyllene oxide evidenced potent cytotoxic activity against HepG2, AGS, HeLa, SNU-1, and SNU-16 cells, with IC50 values of 3.95, 12.6, 13.55, 16.79, and 27.39 uM, respectively.