Objectives To systematically review the efficacy and safety of nalmefene hydrochloride for acute cerebral infarction. Methods PubMed, EMbase, The Cochrane Library, CBM, CNKI, WanFang Data and VIP databases were electronically searched to collect randomized controlled trials (RCTs) on nalmefene hydrochloride for acute cerebral infarction from inception to February 21st, 2018. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software. Results A total of 8 RCTs involving 1 038 patients were included. The results of meta-analyses showed that, compared to the routine treatment group, the nalmefene hydrochloride group was significantly associated with an increased reduction in total effective rate (RR=1.14, 95%CI 1.04 to 1.23, P=0.003), GCS (MD=1.30, 95%CI 0.66 to 1.94, P<0.0001), patient satisfaction (RR=1.26, 95%CI 1.03 to 1.55, P=0.03), cerebral blood flow (MD=5.00, 95%CI 3.81 to 6.19, P<0.05), and cerebral blood volume (MD=0.28, 95%CI 0.23 to 0.32, P<0.05). It was also significantly associated with an reduction of NIHSS, CSS, level of inflammatory factors after treatment in 14 days, level of MMP-9 and mean transit time of contrast medium (P<0.05). However, no significant association was observed between two groups in level of inflammatory factors after treatment in 20 days. For safety outcomes, no significant association was found between two groups in mortality, dizziness, and nausea and vomiting. Conclusions The current evidence indicates that the nalmefene hydrochloride can be used to treat acute cerebral infarction based on routine treatment of acute cerebral infarction, and the safety is relatively good. Due to limited quality and quantity of the included studies, more high quality studies are required to verify above conclusion. © 2019, West China University of Medical Science. All Right reserved.