Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that affects the physiology of multiple joints due to abnormal bone erosion and cartilage deterioration caused by a variety of elements, such as the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) produced by chondrocytes, synovial fibroblasts, and synovial macrophages [1,2]. This process involves cells from the myeloid and leukocyte lineages, including monocytes/macrophages, neutrophils, mast cells, B lymphocytes, and some subsets of T helper cells [3,4]. Moreover, cytokines in the joint space, including tumor necrosis factor-alpha (TNF), interleukin 1 beta (IL-1β), IL-6, and IL-17, contribute to the pleiotropic damage of the joints in RA [5]. Recently, other emerging elements have been documented to be involved in the pathophysiological modulation of RA. In particular, there is the plasminogen activator (PA) complex, a family of proteins that has been identified to carry out this pleiotropic process [6]. Of note, plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in the breakdown of blood clots (fibrinolysis). In detail, the PA system is an extracellular proteolytic enzyme structure divided into two forms, tissue-type PA (tPA) and urokinase PA (uPA), which are expressed during a variety of cellular activities [7]. In particular, the uPA family of proteins is the major constituent of the PA system, which is involved in inflammatory processes, including tissue remodeling as well as tumor progression and metastasis. These proteins are recognized by the uPA receptor (uPAR), which activates diverse intracellular inflammatory pathways [8]. Indeed, uPA–uPAR binding promotes the change of plasminogen to plasmin, which in turn stimulates a succession of proteolytic cascades to destroy extracellular matrix elements. Furthermore, interaction with coreceptors such as integrins and vitronectin promotes recognition (uPAR ligands) [9]. However, in normal physiological conditions, uPA fulfills its function in the tPA presence [10]. In recent years, uPA protease has been strongly implicated in the pathogenetic process and progression of cartilage damage in RA. This physiological process regulates several cellular pathways, including cytokine secretion, cell activation/migration, and fibrinolysis [11,12]. All of these processes begin with an interaction between uPA and its receptor uPAR, which causes tissue remodeling and T cell activation [13]. Moreover, increased uPA expression and decreased tPA expression have been related to the severity of RA disease [14]. In addition, the activity of synovial cells such as macrophages, fibroblast-like synoviocytes (FLS), chondrocytes, and endothelial cells is regulated by the uPA/uPAR interaction, allowing them to secrete a variety of cytokines, chemokines, and growth factors that alter the prognosis of RA [15]. In the absence of macrophage colony-stimulating factor (M-CSF), uPA/uPAR expression suppresses osteoclast differentiation/formation via upregulation of adenosine monophosphate-activated protein kinase (AMPK) [16]. Conversely, other data have demonstrated that in the presence of M-CSF, uPAR promotes osteoclast differentiation via a PI3K/Akt-dependent mechanism [17]. Moreover, other transcription factors (TFs) that it can activate include nuclear factor kappa B (NFB) and nuclear factor activator of T cells 1 (Nfatc1) [17,18].