Objective: Tirofiban plus recombinant tissue plasminogen activator (rtPA) shows good efficacy and safety in treating acute ischemic stroke (AIS) patients, but there is a lack of comprehensive assessment. This meta-analysis aimed to compare the efficacy and safety of rtPA plus tirofiban with rtPA alone in AIS patients. Methods: This meta-analysis retrieved studies comparing rtPA intravenous thrombolysis followed by tirofiban (rtPA+T group) versus rtPA intravenous thrombolysis alone (rtPA group) for AIS patients in Excerpt Medica Database, Web of Science, Cochrane, PubMed, China National Knowledge Infrastructure, Wanfang, and SinoMed until March 2024. Results: Twenty studies with 2048 AIS patients were enrolled in this meta-analysis. National Institute of Health stroke scale (NIHSS) score after treatment was lower in the rtPA+T group than the rtPA group [standardized mean differences (SMD)=-1.41; 95 % confidence interval (CI)=-1.83, -0.98; P<0.001]. The proportion of AIS patients achieving a favorable functional outcome (modified Rankin Scale score <= 2) was increased in the rtPA+T group versus the rtPA group [relative risk (RR)=1.13; 95 % CI=1.05, 1.21; P=0.001]. The incidence of reocclusion was lower in the rtPA+T group than in the rtPA group (RR=0.24; 95 % CI=0.10, 0.59; P=0.002), but the incidence of intracranial hemorrhage (ICH) (RR=0.85; 95% CI=0.51, 1.43), symptomatic ICH (RR=1.10; 95 % CI=0.43, 2.84), and mortality (RR=1.39; 95 % CI=0.53, 3.65) was not different between the two groups (all P>0.05). The stability assessed by sensitivity analysis was good, and no publication bias was found. Conclusion: rtPA plus tirofiban achieves superior efficacy with comparable safety profiles compared to rtPA alone in AIS patients.