Host inflammatory responses are key to protection against injury; however, persistent inflammation is detrimental and contributes to morbidity and mortality. Herein, we demonstrate the anti-inflammatory role of Arteannuin-B(1) and its novel spirocyclic-2-isoxazoline derivative JR-9 and their side effects in acute inflammatory condition in-vivousing carrageenan-induced paw edema, acetic acid-induced writhing and tail immersion. The results show that spirocyclic-2-isoxazoline derivative has potent anti-inflammatory effect as compared to Arteannuin-B with minimal cell toxicity. In addition, the efficacies of these compounds were also validated by computational and histopathological analysis. Our results show that anti-inflammatory response of JR-9significantly reduce the ability of mouse macrophages to produce NO, TNF-α, and IL-6 following LPS-stimulation.