Surgical site infection (SSI) is one of the most common postoperative complications after appendectomy leading to recurrent surgery, prolonged hospital stay, and the use of antibiotics. The burden of surgical site infection varies from 1.2 to 20% across the previously conducted studies. However, there are limited studies available on this problem in Ethiopia. Therefore, this study aimed to assess prevalence of post-appendectomy surgical site infection among children in Amhara region, Ethiopia. A cross-sectional study was employed. The data extraction tool was used to collect data from 423 sampled participants. Simple random sampling technique was used. Data cleaned, coded and entered into Epi Data version 4.6 and exported to STATA version 14.0. The data was presented using table and text forms. The logistic regression model was fitted after checking the required assumptions through Hosmer and lemeshow test to identify predictors of post-operative complications. The bivariable analysis was done to identify associations between dependent and each independent variable. Moreover, variables with P ≤ 0.25 levels in the bivariable analysis were entered into the multivariable analysis. Adjusted odd ratio with 95% CI was used to assess the direction, strength of association and statistical significance. Any statistical test was considered significant at P-value <
0.05. A total of 406 study participants were considered for analysis. The prevalence of surgical site infection was 9.11% (95%CI
6.67%, 12.34%). Having fever (AOR = 2.788, 95%CI (1.10, 7.05)), being taking preoperative antibiotics (AOR = 7.3, 95%CI (2.5, 21)) and having drainage following appendectomy (AOR = 6.3, 95%CI (2.7, 14.7)) were statistically significant predictors of surgical site infection following appendectomy in children. The prevalence of surgical site infection was high as compared the national target. Taking preoperative antibiotics, having fever, and having drainage after operation were significantly associated with surgical site infection. Therefore, a prospective follow up study is important. Those children with appendicitis who presented with a clinical symptom of fever, leaving drainage after procedure and timing of preoperative antibiotics requires special attention of the surgical safety team.