Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has drawn attention for its potential anti-inflammatory and analgesic properties. Scientific interest in PEA for rheumatoid arthritis (RA) arises from its role as an autacoid local inflammation modulator, acting primarily through the peroxisome proliferator-activated receptor alpha (PPAR-α) and potentially other cellular pathways involved in inflammation and pain signaling. Preclinical studies have consistently shown that PEA can reduce inflammation and pain in various animal models of chronic inflammatory conditions, including those that mimic aspects of rheumatoid arthritis. In vitro studies have also demonstrated that PEA can reduce the release of pro-inflammatory cytokines and mast cell degranulation. However, direct clinical evidence in human subjects with RA is sparse. The majority of human studies focus on PEA’s effects in neuropathic pain, osteoarthritis, and other chronic pain conditions, not specifically RA. While a few small clinical studies and case reports suggest PEA may reduce pain and improve quality of life in inflammatory joint disorders, robust randomized controlled trials in RA patients are lacking. Therefore, the use of PEA in RA is scientifically plausible and partially supported by basic and preclinical research, but its efficacy and safety in this specific population have not been firmly established. More high-quality clinical trials are needed to draw definitive conclusions.