<p>Rheumatoid arthritis (RA) is an autoimmune, chronic, inflammatory disease characterized by synovial hyperplasia, bone erosion, progressive joint deterioration, and excruciating joint pain. Worldwide RA prevalence is approximately 0.1–2%, affecting women and elderly population. Limited knowledge of disease pathogenesis causes hindrance in diagnosis and treatment of RA. Deep investigation of RA pathogenesis is deemed, for the development of novel therapies. Among diverse targets for RA, proper functioning of mitochondria is essential for endurance of synovial cells and chondrocytes. Once mitochondria are damaged, these affect immune and non-immune cells in terms of their activation, survival, and differentiation prima to occurrence of RA. An innate immune complex, NLRP3 (NOD-like receptor family pyrin domain-containing 3) inflammasome plays pivotal role in RA pathogenesis through its control on the synthesis of pro-inflammatory cytokines (IL-1β &amp; IL-18) and induction of pyroptotic cell death. Mitochondrial dysfunction is the possible primary cause of NLRP3 inflammasome activation, leading to inflammation and joint destruction in RA. This review emphasizes that how mitochondrial dysregulation affect NLRP3 inflammasome activation and contribute to RA’s inflammatory cascade. It also investigates synthetic and natural substances including Berberine, Ebselen, and Resveratrol that have emerged as promising drug leads for RA by modulating mitochondrial dysfunction and inhibiting NLRP3 inflammasome activation. Furthermore, it concise the evidences from RA-associated animal models explaining beneficial impact of various therapeutic agents in attenuation of inflammation and deterioration of bone and cartilage. Hence, the current review stresses molecular pathways in mitochondrial dynamics and NLRP3 inflammasome activation, as an approach to hone RA treatment goals.</p>