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Abstract Epilepsy is a common disorder with complex inheritance, and its treatment is very unsatisfactory. An association between the GABRG2 C588T polymorphism and genetic generalized epilepsy has been studied by several genetic association studies. However, these results were inconsistent, and the role of GABRG2 in epilepsy treatment remains unknown. To evaluate the role of GABRG2 in epilepsy, we performed meta‐analysis, expression quantitative trait loci analysis, protein–protein interaction analysis, and drug–gene interaction analysis. The combined results indicated that the GABRG2 C588T polymorphism was associated with genetic generalized epilepsy risk under dominant and allelic models (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.02–1.54, p = 0.03, I2 = 0% and OR = 1.21, 95% CI = 1.03–1.42, p = 0.02, I2 = 20%, respectively). In the Asian population, we also found similar results under dominant and allelic models (OR = 1.93, 95% CI = 1.18–3.16, p = 0.009, I2 = 0% and OR = 1.69, 95% CI = 1.20–2.37, p = 0.003, I2 = 11%, respectively). We first found that the GABRG2 C588T polymorphism regulates GABRG2 expression in human brain tissues and that the protein encoded by GABRG2 interacts with targets of approved antiepileptic drugs (AEDs). Interestingly, we also found that GABRG2 itself interacts with approved AEDs. Taken together, the results indicate that the C588T polymorphism might alter the GABAA receptor by modulating GABRG2 gene expression, resulting in increased risk for epilepsy, and that GABRG2 may be a potential therapeutic target for epilepsy.