Background: Although the safety and feasibility of very early rehabilitation for stroke are well recognized, the initiation of rehabilitation is sometimes delayed after thrombolysis. The purpose of this study was to clarify the association between very early rehabilitation and outcomes in acute ischemic stroke patients who received tissue plasminogen activator, using a national inpatient database in Japan. Methods: We identified patients who were admitted to acute-care hospitals with ischemic stroke and were treated with intravenous recombinant tissue plasminogen activator on the same day of stroke onset and received rehabilitation within 3 days from admission. The primary outcome was functional independence on discharge. We compared the outcomes of a very early rehabilitation group with a comparison group. Results: We identified 6,153 eligible patients, of whom 4,266 received very early rehabilitation. The proportion of functional independence on discharge was 41.2 and 36.6% in the very early rehabilitation group and the comparison group, respectively. Multivariable logistic regression analysis showed that the very early rehabilitation was significantly associated with a higher proportion of functional independence after adjustment for confounding factors. There was no significant difference in 7-, 30-, 90-day mortality or incidence of intracerebral hemorrhage between the groups after adjusting for baseline characteristics. Instrumental variable analysis confirmed a higher proportion of functionally independent patients in the very early rehabilitation group. Conclusion: Patients with acute ischemic stroke undergoing very early rehabilitation after thrombolysis were more likely to achieve functional independence without an increase in adverse outcomes.