To investigate the impact of oral antiplatelet medication administration prior to onset on the efficacy and safety of rt-PA intravenous thrombolysis in patients with acute ischemic stroke (AIS). Methods: A retrospective analysis was conducted on 209 AIS patients who underwent rt-PA intravenous thrombolysis at Puren Hospital Affiliated to Wuhan University of Science and Technology between January 2020 and January 2023. Based on whether the patients had taken oral antiplatelet medication within 24 hours before onset, they were divided into two groups: the antiplatelet group (53 patients who were taking antiplatelet medication before thrombolysis) and the non-antiplatelet group (156 patients who did not take antiplatelet medication). The National Institutes of Health Stroke Scale (NIHSS) was used to assess the short-term efficacy before thrombolysis, at 24 hours post-thrombolysis, and at 7 days post-thrombolysis. The modified Rankin Scale (mRS) at 90 days post-thrombolysis was used to evaluate long-term prognosis. The incidence of bleeding at various sites and mortality rates were recorded to assess treatment safety. Results: There were no statistically significant differences in baseline characteristics between the two groups (P>0.05). In the antiplatelet group, the good prognosis rates at 24 hours and 7 days post-thrombolysis were 49.1% (26/53) and 75.5% (40/53), respectively. In the non-antiplatelet group, the corresponding rates were 41.7% (65/156) and 72.4% (113/156). The excellent prognosis rate at 90 days was 54.7% (29/53) and the good prognosis rate was 75.5% (40/53) in the antiplatelet group, compared to 59.0% (92/156) and 80.8% (126/156) in the non-antiplatelet group. There were no statistically significant differences in short-term efficacy and long-term prognosis between the two groups after thrombolysis (P>0.05). The incidence of bleeding was 15.1% in the antiplatelet group and 11.5% in the non-antiplatelet group, while the mortality rates were 5.7% and 1.9%, respectively. There were no statistically significant differences in bleeding incidence and mortality between the two groups (P>0.05). Multivariate Logistic regression analysis showed that the NIHSS score before thrombolysis was a risk factor for long-term prognosis in AIS patients (OR=1.293, 95% CI 1.181～1.415, P<0.001). History of antiplatelet medication use was not associated with long-term prognosis or bleeding in AIS patients (OR=1.182, 95% CI 0.505～2.765, P=0.700). Conclusion: The history of oral antiplatelet medication has no significant impact on the clinical efficacy of intravenous thrombolysis in AIS patients and does not increase the risk of bleeding or mortality after thrombolysis.