Introduction: Piper longum has been studied and found to have potentially beneficial anti-arthritic properties. Consequently, we intended to investigate the effects of an aqueous extract of the fruit of Piper longum on complete Freund's adjuvant-induced arthritic changes in Wistar rats, as well as its interaction with cyclosporine A. Methodology: A total of 48 Wistar rats were divided into 8 groups each containing 6 rats: Group I (control), Group II (Rheumatoid Arthritis control (complete Freund's adjuvant [CFA])), Group III (CFA+ Piper longum 200mg/kg/day), Group IV (CFA+ Piper longum 400mg/kg/day), Group V (CFA+ Cyclosporine A 10mg/kg/day (subtherapeutic dose)), Group VI (CFA+ Piper longum 200mg/kg/day + cyclosporine A 10mg/kg/day), Group VII (CFA+ Piper longum 400mg/kg/day + cyclosporine A 10mg/kg/day) and Group VIII (CFA+ Cyclosporine A 15mg/kg/day (Standarddrug)). They received a normal pellet diet and water ad libitum. They were allowed to get acclimatized to the new environment for 1 week and assessed for 28 days. Arthritis parameters were assessed on the 14th and 28th days. Results: Except for group 1, weight, Proinflammatory cytokine (TNF-), Anti-inflammatory cytokine (IL-10), Nuclear Factor Kappa Beta (NF-), Malondialdehyde (MDA), and Superoxide dismutase (SOD) varied significantly among groups. The arthritis index decreased in all treatment groups. When changes in left and right paw volume were measured, all treatment groups exhibited a significant reduction in left and right paw volume. Similarly, the diameter of the ankle decreased in the treatment groups. Conclusion: In conclusion, the aqueous extract of Piper longum possesses potentially useful anti-arthritic activity.