Abstract Objective This meta-analysis aimed to compare the efficacy and safety of antibiotic treatment and appendectomy for acute uncomplicated appendicitis. Methods We searched the randomized controlled studies (RCTs) comparing appendectomy with antibiotic treatment for uncomplicated acute appendicitis in the electronic database including Pubmed, Embase, Cochrane, Web of Science, CNKI, VIP, and WanFang. The primary outcomes included complication-free treatment success at 1 year, complications, surgical complications, and the complicated appendicitis rates. Secondary outcomes included negative appendicitis, length of hospital stay, the quality of life at 1 month, and the impact of an appendicolith on antibiotic therapy. Results Twelve randomized controlled studies were included. Compared with surgery group, the antibiotic group decreased the complication-free treatment success at 1 year (RR 0.81; 95% CI 0.73–0.91; z = 3.65; p = 0.000). Statistically significance was existed between antibiotic group and surgical group with both surgical types(open and laparoscopic) (RR 0.43; 95% CI 0.31–0.58; z = 5.36; p = 0.000), while no between the antibiotic treatment and laparoscopic surgery (RR 0.72; 95% CI 0.41–1.24; z = 1.19; p = 0.236). There was no statistically significant differences between two groups of surgical complications (RR 1.38; 95% CI 0.70–2.73; z = 0.93; p = 0.353), the complicated appendicitis rate (RR 0.71; 95% CI 0.36–1.42; z = 0.96; p = 0.338), negative appendectomy rate (RR 1.11; 95% CI 0.69–1.79; z = 0.43; p = 0.670), duration of hospital stay (SMD 0.08; 95%CI -0.11-0.27; z = 0.80; p = 0.422), and quality of life at 1 month (SMD 0.09; 95%CI -0.03-0.20; z = 1.53; p = 0.127). However, in the antibiotic treatment group, appendicolith rates were statistically higher in those whose symptoms did not improve (RR 2.94; 95% CI 1.28–6.74; z = 2.55; p = 0.011). Conclusions Although the cure rate of antibiotics is lower than surgery, antibiotic treatment is still a reasonable option for patients with uncomplicated acute appendicitis who do not want surgery without having to worry about complications or complicating the original illness.