The hypoxic microenvironment is a clinicopathological characteristic of many diseases, such as rheumatoid arthritis (RA). As a transcription factor activating the gene expression involved in processes such as cell metabolism and angiogenesis, hypoxia-inducible factor (HIF) has a central function in adaption to altered oxygen tension and even contributes to the progression of related diseases. In RA, HIF induces angiogenesis, cell migration, and cartilage destruction, inhibits the apoptosis of synovial cells and inflammatory cells and initiates glycolysis for energy supply by upregulating specific protein levels. HIF expression in RA can be regulated in both oxygen-dependent and independent fashions, leading to the aggravation of this disease. Therefore, HIF is one of the vital RA mediators. Based on the application of HIF-targeted drug research and development in tumors, HIF is a potential therapeutic target for treating RA.