A lot of previous studies are concerned with the evaluation of the anti-inflammatory activity of medicinal plants because it considered cheap and are believed to possess minimal side effects. Leucaena leucocephala didn’t evaluate globally for its anti-inflammatory effect yet though some of it’s already separated and identified secondary metabolites were studied and proved to exert many pharmacological activities besides their effect on lowering the pro-inflammatory cytokines like TNF-α and IL-6. So, there was an interest to evaluate the biological effect of Leucaena leucocephala as a novel anti-inflammatory agent was the first motivation to start an in vivo study using a rat population. The N-butanol and ethyl acetate extracts were chosen to undergo this study since they contain a lot of the polyphenolic compounds (flavonoids, stilbenes and phenolic acids) which is natural bioactive compounds. Thirty albino rats weighing (150-200) grams of both sexes were used and divided into five groups, each group containing 6 rats: Group I: Negative control, group II: Positive control, group III: Treatment with n-butanol extract, group IV: Treatment with EA extract, group V: Treatment with diclofenac sodium. The oral route of administration using gastric gavage was dependent and for consecutive seven days of supplementation. The induction of inflammation was done by insertion of cotton pellets subcutaneously into the ventral region that is previously shaved and sterilized, with one pellet on each side. So, Leucaena leucocephala proved its novel anti-inflammatory effect by a significant decrease in the inflammation in albino rat models by reducing the percentage of exudate and granuloma and decreasing the serum concentrations of TNF-α and IL-6.