ABSTRACT Gastrointestinal (GI) cancers represent a major global health burden due to their high incidence and mortality. Brusatol has emerged as a promising natural anticancer agent with potent activity against diverse malignancies. It exerts antitumor effects by inhibiting the nuclear factor erythroid 2–related factor 2 (NRF2) signaling pathway, modulating redox homeostasis, and sensitizing tumor cells to oxidative stress and chemotherapeutics. This review summarizes the current understanding of the molecular mechanisms of brusatol in GI cancers, and its synergistic potential with conventional therapies as well as nanotechnology‐based delivery systems. We highlight the future directions for safer and more selective brusatol derivatives for GI cancer therapy.