Post-stroke epilepsy is one of the most significant long-term complications of stroke and substantially worsens functional outcomes and quality of life. Genetic factors may determine individual susceptibility to the formation of an epileptogenic focus following structural brain injury. Objective. To evaluate the prognostic significance of gene polymorphisms related to neuroinflammation, ion channels, and neuroplasticity in the development of symptomatic epilepsy after stroke. Materials and Methods. A total of 124 patients with ischemic and hemorrhagic stroke were included in the study. Genotyping was performed for polymorphisms of IL-1β (–511C/T), IL-6 (–174G/C), TNF-α (–308G/A), SCN1A, GABRA1, and BDNF (Val66Met). Patients were followed prospectively for 12 months. Results. Symptomatic post-stroke epilepsy developed in 26 patients (20.9%). The most significant genetic predictors were the C allele of IL-6, the A allele of TNF-α, and variant forms of SCN1A. The combined predictive model demonstrated high prognostic value (AUC = 0.82). Conclusion. Genetic markers of inflammatory response and neuronal excitability have independent prognostic significance and may be used for risk stratification of post-stroke epilepsy.