Background: Literature shows that serum selenium concentration is low in rheumatoid arthritis (RA) patients. Biochemical properties of nanoparticles (NPs) are depend in its medium dispersed. Biochemical properties could effectively alter the therapeutic potential of NPs. Phytochemicals could serve as suitable medium for dispersion of NPs. P-Coumaric acid (CA) known to have anti-inflammatory activity. Material/Methods: In the present experiment, we investigated the anti-inflammatory effect of SeNPs dispersed in 1% CA against Complete Freund's adjuvant induced RA. Celecoxib was used as a reference drug. Results: Selenium NPs (SeNPs) size is maintained in 1% CA solution. We observed that supplementation with 500 mu g/Kg body weight (b.w.) eNPs significantly restored the levels of thiobarbituric acid reactive substances, COX-2 activity, different antioxidant enzyme activities, and inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6, and MCP-1) in RA rats. The mRNA expression of antioxidant enzymes such as MnSOD, Cu/ZnSOD, ECSOD, CAT, and GPx1 was found to be downregulated, whereas COX-2 was upregulated in RA rats; however, the mRNA expression of CAT, GPx1, and COX-2 reverted back to near normal levels in SeNPs-treated animals. Conclusions: The therapeutic potential of SeNPs was confirmed through histological observation of angle joints in different experimental animals. Our results collectively suggest that SeNPs dispersed in CA can be an effective therapeutic agent for inflammatory disorders like acute gouty arthritis.