Background: Infections are common complications after stroke and associated with unfavorable outcomes. We evaluated the efficacy and safety of prophylactic antibiotics for post-acute stroke infection. Methods: We searched PubMed, Embase, the Cochrane Library, SinoMed, China National Knowledge Infrastructure, and WanFangData from inception to February 15th, 2022. We calculated the pooled risk ratio (RR) and mean differences (MDs) with 95% confidence interval (CI), evaluated the risk of bias and conducted sensitivity analysis with RevMan version 5.4.1 and Stata version 14.0 software. The overall quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results: Twelve studies (4809 participants) were included in this meta-analysis. There was no significant difference in the mortality rate [RR 1.03 (95% Cl: 0.91-1.16)], pneumonia [RR 0.94 (95% CI: 0.79-1.11)], and the incidence of adverse events between the prophylactic antibiotics and control groups. Prophylactic antibiotics significantly reduced the incidence of infections [RR 0.72 (95% Cl: 0.58-0.89)], and urinary tract infections [RR 0.39 (95% Cl: 0.3-0.49)] in patients with acute stroke. We performed a subgroup analysis and found a decreasing trend in pneumonia in patients with early prophylactic use of antibiotics within 24 hours after admission [RR 0.81 (95%CI: 0.62-1.07)] as compared with those using prophylactic use of antibiotics within 48 hours after admission [RR 0.94 (95%CI: 0.79-1.11)]. Conclusions: Prophylactic antibiotics did not significantly reduce the mortality rate and pneumonia in patients with acute stroke but reduced the incidence of infections and urinary tract infections.