The anti-inflammatory activities of ursolic acid (UA) a natural triterpene, copper (Cu), selenium (Se), and zinc (Zn) is well documented. This study focuses on the anti-arthritic synergistic effect of novel compounds encompassing UA+Cu, UA+Se, and UA+Zn, on Freund's complete adjuvant (FCA) arthritic rat model. Lornoxicam (LX) was used as a standard drug for comparative effects. Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate mRNA expression and enzyme-linked immunosorbent assay (ELISA), was used to determine protein levels of LOX and COX-2. Furthermore, in vitro proliferation of Concanavalin A (ConA)-stimulated splenocyte was quantified using an ELISA reader. Acute toxicity of the UA+Cu, UA+Se, and UA+Zn complexes was assessed. Combination of UA with Cu, Se, Zn resulted in significantly decreased expression of NFĸB, TNF-α, TLR2, and TLR4, on the other hand IL-4, IL-10, and IL-13 expression was significantly increased. Additionally, UA complexes significantly reduced serum C-reactive protein (CRP), serum nitric oxide (NO), serum COX-2, and 5-LOX. UA+Cu, UA+Se, and UA+Zn suppressed ConA-specific splenocyte proliferation. UA+Cu, UA+Se, UA+Zn showed no hepatotoxic and nephrotoxic potential. Overall, results reflected that novel compound, UA+Cu, UA+Se, and UA+Zn have synergistic effect as compared to Cu, Se, and Zn alone, and their results were comparable with standard drug LX.