Background and Aim: In addition to free radicals such as Nitric Oxide (NO), inflammation is one of the most important pathophysiological causes of peritonitis. Over thousands of years, Nigella Sativa (NS) and Silybum Marianum (SM) are two plants known for their anti-oxidant and anti-inflammatory properties. However, the effect of its compound is unclear. Thus, in this study, we evaluated the anti-inflammatory effect of NS and SM extracts and their combination on inflammatory diseases like thioglycollate peritoneal. Methods & Materials: Alcoholic extracts of SM and NS were obtained by the soxhlet method. Male Balb/C mice were divided into 5 groups and gavage orally for 14 days with SM, NS, the mixture of extracts of these two, DMSO 30% as the control group, and dexamethasone as the positive control group. The safety profile and acute toxicity in mice were assessed. On day 10, acute peritonitis was induced by thioglycollate 3%. Finally, the total anti-oxidant power and NO concentration were measured by FRAP and Griess method, respectively, in the serum of treated mice. Ethical Considerations: All experimental process was performed following the guidelines according to the Animal Ethics Committee of Arak University of Medical Sciences (IR.ARAKMU.REC.1397.359). Results: Acute toxicity test showed no significant changes in weight and physical appearance of the mice. However, the extract and their mixture decreased NO level significantly (P=0.000) in serum. Also, the mixture significantly increased total anti-oxidant power (P=0.015). Conclusion: Results showed that the SM and NS extract mixture demonstrated anti-inflammatory activity, inhibiting inflammatory mediators such as NO and increasing anti-oxidant power, thus supporting its therapeutic potential in slowing down inflammatory processes in inflammation disorders.