Our data highlighted for the first time that an indirect inhibition of phospho(Tyr705)-STAT3 by the lowering of γ-H2AX, likely as a consequence of the activation of a DNA repair response, can be involved in the chemosensitizing and chemopreventive effects of β-caryophyllene towards doxorubicin in cancer and normal cholangiocytes. Here, STAT3 is linked to cancer.