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Introduction: Thrombolytic therapy for the indication of acute ischemic stroke (AIS) can increase the risk of major bleeding complications, including symptomatic intracranial hemorrhage (sICH). However, the incidence of sICH associated with intravenous (IV) tenecteplase is not well characterized in the literature compared to IV alteplase. This study aims to evaluate and compare the incidence of sICH following administration of IV alteplase versus IV tenecteplase in patients with AIS. Methods: This was a single center retrospective chart review of patients who presented to Community Regional Medical Center with AIS, who were subsequently treated with either alteplase (August 9, 2022 to August 8, 2023) or tenecteplase (August 9, 2023 to August 8, 2024). The primary outcome was the percentage of patients who received an IV thrombolytic for the treatment of AIS that subsequently developed sICH. Secondary outcomes include in-hospital all-cause mortality, incidences of angioedema, functional outcomes using the Modified Rankin Scale (mRS) score and other major bleeding as defined by the International Society of Thrombosis and Haemostasis (ISTH). Results: A total of 73 patients were included in the analysis; 44 patients received alteplase and 29 patients received tenecteplase. Baseline characteristics were comparable between both groups. Notably, only two patients in the alteplase group underwent mechanical thrombectomy; none were performed in the tenecteplase group. The overall rate of sICH was 4.5% in the alteplase group and 3.4% in the tenecteplase group (P = 1). The rates of other bleeding outcomes were comparable between groups, including petechial hemorrhages (6.8% vs 3.4%, P = 1), asymptomatic intracranial hemorrhage (2.3% vs 3.4%, P = 0.73), and major bleeding per ISTH criteria (9.1% vs 3.4%, P = 0.64). Functional outcomes were similar, with a median mRS score of 1.5 (IQR 1–4) in the alteplase group and 1 (IQR 1–2.8) in the tenecteplase group (P = 0.21). Mortality was also comparable (4.5% vs 3.4%, P = 1), with no documented cases of angioedema. Conclusions: Symptomatic, asymptomatic, and petechial hemorrhagic transformation rates were comparable between alteplase and tenecteplase in the treatment of AIS, consistent with findings from prior major clinical trials.