Rheumatoid arthritis (RA) is a systemic and chronic autoimmune inflammatory disorder affecting multiple joints. Various cytokines, chemokines and growth factors synergistically modulate the joint physiology leading to bone erosion and cartilage degradation. Other than these conventional mediators that are well established in the past, the newly identified plasminogen activator (PA) family of proteins have been witnessed to possess a multifactorial approach in mediating RA pathogenesis. One such family of proteins comprises of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR)/soluble-type plasminogen activator receptor (suPAR). PA family of proteins are classified into two types namely: uPA and tissue type plasminogen activator (tPA). Both these subtypes have been implicated to play a key role in RA disease progression. However during RA pathogenesis, uPA secreted by neutrophils, chondrocytes, and monocytes are designated to interact with uPAR expressed on macrophages, fibroblast-like synoviocytes (FLS), chondrocytes and endothelial cells. Interaction of uPA/uPAR promotes the disease progression of RA through secretion of several cytokines, chemokines, growth factors and matrix metalloproteinases (MMPs). Moreover, uPA/uPAR initiates inflammatory responses in macrophages and FLS through activation of PI3K/Akt signaling pathways. Furthermore, uPAR plays a dual role in osteoclastogenesis under the presence/absence of growth factors like monocyte-colony stimulating factor (M-CSF). Overall, this review emphasizes the role of uPA/uPAR on various immune cells, signaling pathways and osteoclastogenesis involved in RA pathogenesis.