Osteosarcoma is a highly malignant bone tumor that is resistant to radiotherapy and is associated with poor treatment outcomes and prognoses. Understanding the mechanisms of radioresistance and finding strategies to enhance the radiosensitivity is crucial for improving clinical efficacy. The aim of this review was to address the approaches for enhancing the efficacy of radiotherapy in osteosarcoma, thereby improving patient outcomes. Specifically, we have focused on the mechanisms of radiosensitization and the relationship between drugs that enhance radiosensitivity and cancer. These mechanisms involve a delay in DNA damage repair, promotion of apoptosis, inhibition of angiogenesis, and regulation of the tumor microenvironment. In addition, we have summarized the effects of these drugs on the proliferation, migration, invasion and apoptosis of osteosarcoma cell lines. Finally, we have discussed the therapeutic effects and adverse reactions of these drugs in other cancers, providing valuable guidance for clinical treatment strategies tailored to patients with osteosarcoma.