Accurate and timely diagnosis of appendicitis in children can be challenging, which leads to delayed admittance or misdiagnosis that may cause perforation. Surgical management involves the elimination of the focus (appendectomy) and the reduction of the contamination with peritoneal irrigation to prevent sepsis. However, the validity of conventional irrigation methods is being debated, and novel methods are needed. In the present study, the use of cold plasma treated saline solution as an intraperitoneal irrigation solution for the management of acute peritonitis was investigated. Chemical and in vitro microbiological assessments of the plasma-treated solution were performed to determine the appropriate plasma treatment time to be used in in-vivo experiments. To induce acute peritonitis in rats, the cecal ligation and perforation (CLP) model was used. Sixty rats were divided into six groups, namely, sham operation, plasma irrigation, CLP, dry cleaning after CLP, saline irrigation after CLP, and plasma-treated saline irrigation after CLP group. The total antioxidant and oxidant status, oxidative stress index, microbiological, and pathological evaluations were performed. Findings indicated that plasma-treated saline contains reactive species, and irrigation with plasma-treated saline can effectively inactivate intraperitoneal contamination and prevent sepsis with no short-term local and/or systemic toxicity.