Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to the destruction of peripheral joint cartilage and bone tissue. Despite the advent of biological therapies in the past decades, the complete remission of RA patients is still out of reach. Therefore, the search for novel therapeutic approaches is still open in the field of RA. Proteasome inhibitors (PIs) were originally designed to be used in hematological malignancies like multiple myeloma. However, evidence has shown that they are potent inhibitors of the NF-κB pathway, which plays a pivotal role in inflammatory processes and RA. Furthermore, inhibition of cell activation and induction of apoptosis was also reported about PIs. In the present review, we summarize the current knowledge about the potential effects of PIs in RA based on reports from animal and human studies. We believe that there is substantial potential in the use of PIs in RA therapy either alone or in combination with the medications already used.