Rheumatoid arthritis (RA) is an incurable debilitating disease which attack the joints and impair quality of life. Antrocaryon micraster is used to treat RA in African traditional medicine. However, its anti-arthritic activity has not been pharmacologically studied. This study therefore, reports the anti-arthritic and anti-oxidant activities of A. micraster seed extract and its fractions. The seed extract (ASE) was produced by soxhlet extraction and partitioned into petroleum ether (ASEP), ethyl acetate (ASEE) and aqueous (ASEA) fractions. The total polyphenolic content, DPPH anti-oxidant activity and in vitro arthritic activity using the protein denaturation assay were evaluated for ASE and its fractions. The arthritic activity of the crude extract (ASE) and its most effective fraction (ASEA), in the in vitro assay, were then evaluated against CFA-induced arthritis in rats. The polyphenolic constituent of ASE was estimated to be 13.00 ± 0.00 mg/100 mg of GAE. ASEA contained the highest quantity of polyphenolic constituents (10.76 ± 0.00 mg/100 mg of GAE) among the fractions of the extract. ASE and ASEA produced profound anti-oxidant activity (IC50 = 20.17 ± 1.291 and 19.35 ± 0.865 respectively) which were similar to that of ascorbic acid (IC50 = 17.35 ± 0.500) in the DPPH free radical scavenging assay. Furthermore, in vitro anti-arthritic activity of ASEA was 13.63 and 5.75 times higher than the anti-arthritic activity of the crude extract and diclofenac sodium respectively. In the CFA-induced arthritis assay, both ASE and ASEA significantly (P < 0.001) inhibited cachexia, paw edema, infiltration of inflammatory cells, pannus formation and synovium damage. These results indicates that A. micraster seed extract and its fractions possessed significant anti-arthritic activity via inhibition of oxidative stress, inflammation, protein denaturation, infiltration of inflammatory cells and synovium injury due to its constituents such as polyphenols and phytosterols.