Introduction: Patients discharged against medical advice have been shown to have worse outcomes across a host of different conditions. However, risk factors related to increased odds of discharge against medical advice remain understudied in patients who suffer from acute cerebral infarction. Methods: We retrospectively examined the 2019 National Emergency Department Sample Database for stroke patients. Multivariable logistic regression was used to estimate associations between patient- and hospital-level factors and the outcome of discharge against medical advice. Results: Of the 603,623 encounters for acute ischemic stroke, 8,858 (1.5%) were discharged against medical advice. Predictors of discharge against medical advice were lower income quartile and having either Medicaid insurance (odds ratio [OR] 1.32, 95% confidence interval [CI]: 1.10–1.58) or being uninsured (OR 1.28, 95% CI: 1.03–1.58). Vascular comorbidities associated with discharge against medical advice included prior tobacco use (OR 1.60, 95% CI: 1.45–1.78) and coronary artery disease (OR 1.19, 95% CI: 1.04–1.35). Treatment with thrombectomy (OR 0.33, 95% CI: 0.13–0.78) or systemic thrombolysis (OR 0.39, 95% CI: 0.23–0.66) was inversely associated with discharge against medical advice. A high modified Charlson comorbidity index (3+ vs. 0, OR 0.49, 95% CI: 0.42–0.56) was also associated with a lower odds of discharge against medical advice. Presenting to a Northeastern hospital had the highest rate of discharge against medical advice, when compared to other regions (p < 0.05). Conclusions: Certain patient-level, socioeconomic, and regional factors were associated with discharge against medical advice following acute stroke. These patient- and systems-level factors warrant heightened attention in order to optimize acute care and secondary prevention strategies.