Rheumatoid arthritis (RA) is a refractory chronic autoimmune disease, and there is an urgent demand for safe and efficient natural therapeutic alternatives. This study aimed to investigate the anti-arthritic efficacy and underlying molecular mechanism of corn tripeptide Leu-Pro-Pro (LPP). In vitro experiments verified that compared with structurally homologous Ile-Pro-Pro and Val-Pro-Pro, LPP significantly inhibited the proliferation and inflammatory activation of HFLS-RA and RAW264.7 cells, and displayed favorable biosafety without damaging normal somatic cells. In vivo animal assays demonstrated that LPP could dose-dependently reduce joint swelling degree and arthritis clinical scores, remarkably improve pathological changes of joint tissues, inhibit synovial hyperplasia and cartilage degradation, ameliorate trabecular bone microstructure damage, and restore the disordered secretion of multiple inflammatory cytokines.