Osteoarthritis is a chronic degenerative joint disorder that significantly impairs the quality of life of millions of patients and for which there is no reliable cure to date, showing the crucial need for new, effective treatments capable of alleviating this disease. Numerous studies have evidenced the critical roles played by synovial cells during the progression of the disease, including synovial macrophages and synovial fibroblasts. In response to the altered osteoarthritic environment, synovial macrophages undergo polarization towards a pro-inflammatory M1 phenotype with the secretion of inflammatory mediators and cartilage-degrading enzymes (versus an anti-inflammatory M2 phenotype) while synovial fibroblasts become inappropriately activated, producing inflammatory mediators and undergoing abnormal cell proliferation and migration that contribute to synovial fibrosis, aggravate inflammation, and promote angiogenesis, all exacerbating the disease. Regulating the polarization of synovial macrophages and preventing the abnormal activation of synovial fibroblasts may therefore provide adapted strategies to counteract the progression of osteoarthritis. This review recapitulates the roles of synovial cells in the disease and describes the potential of classical and more highly innovative treatments to target synovial cells in vivo as a means to manage the progression of osteoarthritis.