The current standard of practice for patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator (tPA) requires critical monitoring for 24-hours post-treatment due to the risk of symptomatic intracranial hemorrhage (sICH). This is a costly and resource intensive practice. In this study, we evaluated the safety and efficacy of this standard 24-hour ICU monitoring period compared with a shorter 12-hour ICU monitoring period for minor stroke patients (NIHSS 0-5) treated with tPA only. Stroke mimics and those who underwent thrombectomy were excluded. The primary outcome was length of hospital stay. Secondary outcome measures included sICH, deep venous thrombosis (DVT), pulmonary embolism (PE), pneumonia, favorable discharge to home or acute rehabilitation, readmission within 30 days, and favorable functional outcome defined as modified Rankin scale (mRS) of 0-2 at 90 days. Of the 122 patients identified, 77 were in the 24-hour protocol and 45 were in 12-hour protocol. There was significant difference in length of hospital stay for the 24-hour ICU protocol (2.8 days) compared with the 12-hour ICU protocol (1.8 days) ( < 0.001). Although not statistically significant, the 12-hour group had favorable rates of sICH, 30-day readmission rates, favorable discharge disposition and favorable functional outcome. Rates of DVT, PE and aspiration pneumonia were identical between the groups. Compared with 24-hour ICU monitoring, 12-hour ICU monitoring after thrombolysis for minor acute ischemic stroke was not associated with any increase in adverse outcomes. A randomized trial is needed to verify these findings.