<b><i>Background:</i></b> Due to the high post-stroke frequency of dysphagia, dysarthria, and aphasia, we developed comprehensive neuroanatomical, clinical, and demographic models to predict their presence after acute ischemic stroke. <b><i>Methods:</i></b> The sample included 160 randomly selected first-ever stroke patients with confirmed infarction on magnetic resonance imaging from 1 tertiary stroke center. We documented acute lesions within 12 neuroanatomical regions and their associated volumes. Further, we identified concomitant chronic brain disease, including atrophy, white matter hyperintensities, and covert strokes. We developed predictive models using logistic regression with odds ratios (OR) and their 95% confidence intervals (95% CI) including demographic, clinical, and acute and chronic neuroanatomical factors. <b><i>Results:</i></b> Predictors of dysphagia included medullary (OR 6.2, 95% CI 1.5–25.8), insular (OR 4.8, 95% CI 2.0–11.8), and pontine (OR 3.6, 95% CI 1.2–10.1) lesions, followed by brain atrophy (OR 3.0, 95% CI 1.04–8.6), internal capsular lesions (OR 2.9, 95% CI 1.2–6.6), and increasing age (OR 1.4, 95% CI 1.1–1.8). Predictors of dysarthria included pontine (OR 7.8, 95% CI 2.7–22.9), insular (OR 4.5, 95% CI 1.8–11.4), and internal capsular (OR 3.6, 95% CI 1.6–7.9) lesions. Predictors of aphasia included left hemisphere insular (OR 34.4, 95% CI 4.2–283.4), thalamic (OR 6.2, 95% CI 1.6–24.4), and cortical middle cerebral artery (OR 4.7, 95% CI 1.5–14.2) lesions. <b><i>Conclusion:</i></b> Predicting outcomes following acute stroke is important for treatment decisions. Determining the risk of major post-stroke impairments requires consideration of factors beyond lesion localization. Accordingly, we demonstrated interactions between localized and global brain function for dysphagia and elucidated common lesion locations across 3 debilitating impairments.