Aims: This study evaluated the effect of the aqueous fraction of Justicia secunda Vahl leaves on selected inflammatory markers Tumor necrosis factor alpha (TNF-α), nuclear factor–kappa B (NF-κB), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) and its possible mechanism of action. Study Design: J. secunda aqueous leaf fraction (JSALF) was tested on carrageenan, arachidonic and Complete Freund’s Adjuvant (CFA) induced rat paw inflammation models, respectively. Methodology:  Ninety male albino rats (Wistar strain) were randomly distributed into 6 groups of 5 rats each. Group I: normal, administered with 1 mL NaCl, Group II: untreated control, no treatment, Group III: administered with 10 mg/kg body weight (b.wt.) diclofenac sodium (reference drug), Group IV, V, and VI: administered with 200, 400 and 600 mg/kg b.wt. J. secunda leaf aqueous fraction (JSALF), respectively. TNF-α, NF-κB, IL-6 and COX-2 levels were analyzed using enzyme-linked immunosorbent assays (ELISA). Gas Chromatography-Mass Spectrometry (GC-MS) analysis was carried out. Results: JSALF treated animals had significantly (P < .05) suppressed carrageenan, arachidonic and CFA-induced paw edema when compared with untreated control animals. Serum levels of TNF-α, NF-κB, IL-6 and COX-2 were significantly reduced (P < .05) in JSALF-treated animals. GC-MS detected 10 suspected anti-inflammatory compounds. Conclusion: Findings from this study indicate that J. secunda aqueous leaf fraction substantially suppressed pro-inflammatory mediators and COX-2 pathways in arthritic rats which justifies its folkloric use in the management of inflammatory diseases.