Ischemic stroke is a common neurological emergency associated with high mortality. Identifying predictors of in-hospital mortality in ischemic stroke may help healthcare professionals develop appropriate treatment plans and improve patient outcomes. We conducted a retrospective study using discharge records from a single center in Italy to investigate the effects of age, length of stay, thrombolysis, thrombectomy, and disease severity on the likelihood of in-hospital mortality in patients with ischemic stroke. The logistic regression model was statistically significant (χ2 = 95.90, p < .001) and showed a good fit (Nagelkerke R square = 0.303). Age and severity of illness were positively associated with mortality, with each unit increase in age associated with a 5.9% increase in the odds of mortality, and higher severity of illness associated with a nearly 4.8-fold increase in the odds of mortality. Thrombolysis was inversely associated with mortality, with treated patients having approximately 38.5% lower odds of mortality. Thrombectomy showed a trend toward a reduced risk of mortality, although this was not statistically significant. The results suggest that age, disease severity, and thrombolysis are important predictors of in-hospital mortality in patients with ischemic stroke. These findings underscore the importance of individualized risk assessment and targeted interventions. Timely thrombolysis emerges as a potentially life-saving strategy, underscoring the importance of efficient stroke care protocols. By elucidating the predictive factors for in-hospital mortality, this research improves the understanding of ischemic stroke management and paves the way for more effective and patient-centered approaches.