Background: Mortality remains a substantial problem after acute ischemic stroke, despite advances in acute stroke treatment over the past three decades. Mortality is particularly high among patients with Total Anterior Circulation Stroke (TACS), generally representing patients with middle cerebral artery occlusions. Notably however, these patients also stand to benefit most from new therapies including endovascular thrombectomy (EVT). In this study, we aimed to examine temporal trends in, and factors associated with, 30-day in-hospital mortality after TACS. Methods: Information on all patients with community-onset TACS from 1994 through 2019 was extracted from a prospective acute stroke registry. Multivariate analysis was performed on the primary outcome of 30-day in-hospital mortality, as well as secondary functional outcomes. Results: We studied 1106 patients hospitalized for community-onset TACS, 456 (41%) of whom experienced 30-day in-hospital mortality. Over the 25 years of observation, 30-day in-hospital mortality rose and then fell. Increased odds of mortality was associated with age and stroke severity. Decreased odds of mortality was associated with alteplase therapy and EVT, as well as presentation to hospital more than 12 hours after stroke onset. Treatment with alteplase, EVT, or both was associated with higher odds of functional independence and discharge home, and shorter lengths of stay in acute care. Conclusions: Patients receiving alteplase, EVT, or both had lower 30-day in-hospital mortality and better functional outcomes than those who were untreated. These observational data demonstrate the benefits of recanalization therapy in routine clinical practice.