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Health-related quality of life (HRQoL) is a central outcome in epilepsy care, but existing tools are either lengthy, too brief, or lack sensitivity to epilepsy-specific concerns. This study developed and validated the 15-item Quality of Life in Epilepsy Scale (QOLIE-15) and examined sociodemographic, socioeconomic, clinical, and psychosocial determinants of HRQoL. A cross-sectional study was conducted among adult patients with epilepsy recruited from community pharmacies and a primary healthcare center. Participants completed the QOL assessment alongside established measures of medication adherence, adverse events, cognition, anxiety, and stigma. The dataset was randomly split for exploratory and confirmatory factor analysis (EFA and CFA). Reliability, convergent, concurrent, and criterion validity were assessed. Measurement invariance was tested across gender, seizure characteristics, and seizure control. Multivariable linear regression identified independent predictors of QOLIE-15 scores. The study included 649 patients. EFA supported a stable 5-factor structure, with sampling adequacy confirmed by KMO = 0.875 and Bartlett’s test (P < 0.001). CFA demonstrated excellent fit (CFI = 0.978, TLI = 0.972, RMSEA = 0.041, SRMR = 0.034). Internal consistency was high (α = 0.906, ω = 0.929). The QOLIE-15 correlated strongly with QOLIE-31 (r = 0.875) and showed excellent criterion validity, with a cut-off of 44.5 yielding sensitivity of 88.8% and specificity of 82.0%. Measurement invariance was established across key subgroups. In multivariable analysis, lower QOL was independently associated with uncontrolled seizures (B = − 1.53), adverse drug effects (B = − 0.10), stigma (B = − 0.38), cognitive complaints (B = − 0.28), anxiety (B = − 0.52), and higher household crowding (B = − 0.77). The QOLIE-15 is a valid, reliable, and practical instrument capturing epilepsy-specific HRQoL. It balances brevity with multidimensionality, and its invariance and robust psychometric properties support application in clinical practice and research. Independent determinants highlight the importance of addressing seizure control, treatment tolerability, stigma, cognition, and anxiety in epilepsy care.