Osteoarthritis (OA) is the most common joint disorder worldwide, and it has an enormous socioeconomic impact both in the United States and throughout the world. The degree of articular inflammation is usually associated with the disease’s progression, indicating that this process could contribute to articular damage. IL-1 beta and anti-TNF alpha are the two major cytokines players in the physiopathology of OA. Hence, we aimed to review the current literature on the effects of IL-1 and TNF-alpha neutralization as a new OA therapy. In vitro and experimental models showed a reduction in cartilage destruction with IL-1 inhibition therapy by IL-1 receptor antagonists (IL-1Ra). Despite this favorable evidence in animal models, studies on the inhibition of IL-1R in humans are still scarce. Although there is clear evidence that TNF-alpha plays a role in the pathophysiology of OA, only a few experimental trials have investigated the efficacy of blocking this pro-inflammatory cytokine in the treatment of OA. So far, the few studies available in humans using anti-TNF-alpha and IL-1 receptor antagonist are not remarkable, suggesting that further investigation and new therapeutic approaches are needed.