The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C > T is significantly associated with altered concentration–dose ratios of CBZ (CDR_CBZ) (CC vs. CT, OR = 0.25 (95% CI: 0.08–0.42), P = 0.004), and EPHX c.416A > G gene polymorphism may also significantly adjusted the concentration–dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDR_CBZD) (AA vs. GG, OR = 0.48 (95% CI: 0.01–0.96), P = 0.045; AG vs. GG, OR = 0.68 (95% CI: 0.16–1.20), P = 0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDR_CBZD:CDR_CBZE) (AG vs GG, OR = 0.83 (95% CI: 0.31–1.36), P = 0.002). Furthermore, ABCB1 c.3435C > T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR = 1.78 (95% CI: 1.17–2.72), P = 0.008; CT vs TT, OR = 1.60 (95% CI: 1.12–2.30), P = 0.01; CC + CT vs TT, OR = 1.61 (95% CI: 1.15–2.26), P = 0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C > T and EPHX1 c.416A > G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence.