Hypoxia is an intrinsic characteristic of many malignant solid tumors, contributing largely to tumor progression and metastasis, as well as resistance to most standard therapeutic modalities, such as radiotherapy and chemotherapy. It is critically important to develop novel therapeutic modalities for hypoxic tumors. Currently, due to the highly efficient oxidative damage to tumor cells, the free-radical-mediated treatments of hypoxic tumors are of great interest. In this review, we start with the description of the physicochemical and biological characteristics of hypoxic tumor tissues. And then, the construction principles of oxygen-centered, carbon-centered and other atom-centered free-radical based hypoxic tumor therapies are discussed in detail, as well as the corresponding application examples. Moreover, current limitations and future prospects of free radical-mediated hypoxic tumor therapy are discussed. This review is expected to serve as an up-to-date compilation, advancing the development of hypoxic tumor therapy.