Background: Xanthorrhizol (XTZ), a bisabolene sesquiterpenoid, is abundantly found in the plant Curcuma xanthorrhiza Roxb. Traditionally, C. xanthorrhiza is widely used for the treatment of different health conditions, including common fever, infection, lack of appetite, fatigue, liver complaints, and gastrointestinal disorders. XTZ exhibits wide-ranging pharmacological activities, including anticancer, antioxidative, anti-inflammatory, antimicrobial, and antidiabetic activities, in addition to a protective effect on multiple organs. The present review provides detailed findings on the anticancer activities of XTZ and the underlying cellular and molecular mechanisms. Methods: Literature was searched systematically in main databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with keywords “tumor AND xanthorrhizol” or “cancer AND xanthorrhizol”. Results: Studies show that XTZ has preventive and therapeutic activities against different types of cancer, including breast, cervical, colon, liver, lung, oral and esophageal, and skin cancers. XTZ regulates multiple signaling pathways that block carcinogenesis and proliferation. In vitro and in vivo studies showed that XTZ targets different kinases, inflammatory cytokines, apoptosis proteins, and transcription factors, leading to the suppression of angiogenesis, metastasis, and the activation of apoptosis and cell cycle arrest. Conclusion: The potential anticancer benefits of XTZ recommend further in vivo studies against different types of cancer. Further, XTZ needs to be confirmed for its toxicity, bioavailability, protective, antifatigue, and energy booster activities. Future studies for the therapeutic development of XTZ may be directed to cancer-related fatigue.