For the prevention of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites, prophylactic antibiotics are recommended as a standard regimen. This study aimed to assess the efficacy of norfloxacin (N), ciprofloxacin (C), trimethoprim–sulfamethoxazole (T-S), and rifaximin (R) in the prevention of SBP. We searched the electronic databases including PubMed, Cochrane Library, Embase, and Web of Science from inception till 1 August 2018. The randomized-controlled trials that compared N, C, T-S, R, and placebo (P) were identified. A network meta-analysis (NMA) was carried out using the software STATA 14.0 and Revman 5.3. We included 16 studies involving 1984 participants in the NMA for SBP prevention. The NMA results showed that, compared with those treated with P (reference), patients treated with C, N, or R had a lower incidence of SBP and mortality. Similarly, the incidences of SBP and mortality for R were lower than those for N. The probabilities of ranking results showed that R ranked first with respect to the outcomes of the incidence of SBP and mortality. According to our results, R seemed to be the optimal regimen for protecting against SBP in patients with cirrhosis and ascites. However, considering the limitations of our study, additional high-quality studies are required in this respect.