Background The use of oral (PO) antibiotics following a course of certain intravenous (IV) antibiotics is proposed in order to avoid the complications of IV medications and to decrease the cost. However, the efficacy and safety of sequential IV/PO antibiotics is unclear and requires further study. Methods The databases, including PubMed, EMBASE and Cochrane Library, were searched. Studies comparing outcomes in patients with perforated appendicitis receiving sequential IV/PO and PO antibiotics therapy were screened. The Newcastle-Ottawa Scale (NOS) and the Jadad score were used to evaluate the quality of the cohort and the randomized controlled portions of the trial, respectively. Statistical heterogeneity was assessed using the I-2 value. A fixed or random-effect model was applied according to the I-2 value. Results Five controlled studies including a total of 580 patients were evaluated. The pooled estimates revealed that sequential IV/PO antibiotic therapy did not increase the risk of complications, with a risk ratio (RR) of 0.97 (95% CI 0.51-1.83, P = 0.93) for postoperative abscess, 1.04 (95% CI 0.25-4.36, P = 0.96) for wound infection and 0.62 (95% CI 0.33-1.16, P = 0.13) for readmission. Conclusions Our study demonstrates that sequential IV/PO antibiotic therapy is noninferior to IV antibiotic therapy regarding postoperative abscess, wound infection and readmission.