The current investigation was undertaken to determine the anti-inflammatory and antioxidant effects of Paederia foetida Linn. (PF) along with its mechanism of action when implemented in tissue protection. HPTLC was used in the identification of the compound quercetin, while in vitro analysis confirmed the significance of the antioxidant and anti-inflammatory action of PF. We initially demonstrated the in vivo anti-inflammatory effect of PF, evaluating it against a variety of phlogistic agents as well as turpentine oil, prostaglandin and arachidonic acid. Groups of rats, fasted overnight, were treated as follows: Group I: normal control (vehicle), Group II: PF (100 mg kg(-1)), Group III: arthritic control (CFA only, 0.05 ml), Group IV, V, VI: CFA (0.05 ml) + PF (25, 50 and 100 mg kg(-1)) and Group VII: CFA (0.05 ml) + indomethacin (10 mg per kg b.w.). PF significantly protected against paw edema, arthritic index and body weight alteration induced by Complete Fruend's Adjuvant (CFA). Other observations, like histological and macroscopic changes, were observed in CFA induced inflammation in knee joints. Subcutaneous administration of CFA was accompanied by proinflammatory cytokine status, as appraised by the amplification of interleukin-2 (IL-2), interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α); oxidative stress status was estimated by the enhancement of the level of lipid peroxidation (LPO) and the depletion of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH). Pre-treatment with PF significantly (P < 0.001) protected against CFA induced oxidative stress and proinflammatory cytokines. More prominently, CFA administration augmented tissue and plasma superoxide (O2) and hydrogen peroxide (H2O2) levels, while the PF pre-treatment significantly (P < 0.001) reversed all CFA induced intracellular interruption. Following CFA induced arthritis, PF was tested for its free radical scavenging activity against the DPPH and ABTS radicals and its inhibitory proficiency against COX-1 and COX-2 in vitro. Considering the above, the current research confirmed momentous protection against CFA induced arthritis, which could be attributed to its anti-inflammatory and pro-oxidant nature.