<p>Epilepsy is a complex neurological disorder shaped by oxidative stress, imbalances in trace elements, and psychological distress, yet the mechanisms linking these factors to seizure severity and psychiatric outcomes remain poorly understood. This study investigated their interplay through clinical, biochemical, and in silico approaches. A cross sectional analysis was conducted on 200 epilepsy patients and 200 controls with comparable age and sex distributions. Psychological distress was measured using the Depression Anxiety Stress Scale-21 (DASS-21). Serum levels of copper (Cu²⁺), zinc (Zn²⁺), selenium (Se²⁻), iron (Fe²⁺), chromium (Cr³⁺), and magnesium (Mg²) were quantified via atomic absorption spectrophotometry, while oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were assessed by ELISA. Hierarchical regression identified predictors of stress and anxiety, and molecular docking was employed to evaluate interactions of Cu²⁺, Zn²⁺, Se²⁻, and MDA with SOD. Results revealed that epilepsy patients had significantly higher stress, anxiety, depression, Cu²⁺, and MDA levels, along with reduced Zn²⁺, Se²⁻, SOD, and GSH. Regression analyses indicated that Cu²⁺ and MDA were positive predictors of psychological distress, while Zn²⁺, Se²⁻, and SOD exerted protective effects. Docking studies demonstrated strong binding of Cu²⁺ and MDA to SOD, potentially impairing its activity, whereas Zn²⁺ and Se²⁻ promoted stabilization of antioxidant defenses. These findings suggest that trace element dysregulation and oxidative stress contribute to both seizure pathology and psychiatric comorbidities, reinforcing a cycle of neuronal excitatory imbalance, and psychological vulnerability. Integrating antioxidant based therapies and trace element correction with mental health monitoring may improve personalized management of epilepsy. This study is distinctive in combining clinical, biochemical, psychological, and molecular docking analyses to unravel the synergistic effects of trace elements and oxidative stress on epilepsy outcomes.</p> Graphical Abstract <p></p>