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Although numerous studies have explored the maternal genetic contributions to Congenital Heart Disease (CHD), their findings remain inconsistent. This study aimed to investigate the association between maternal gene polymorphisms and neonatal CHD risk in the Chinese Han population from southern Fujian. We conducted a hospital-based case–control study between January 2023 and December 2024, involving 155 mothers of neonates with CHD and 160 healthy controls. Polymorphisms in MTHFR (rs1801133 and rs1801131) and MTRR (rs1801394) were genotyped using Sanger sequencing. Our study showed that maternal polymorphism of MTHFR at rs1801133 was associated with a significantly increased risk of neonata CHD in the crude analysis (OR = 1.665, 95%CI: 1.168–2.371; P = 0.005, FDR_P = 0.018), which remained robust after adjusting for maternal age (OR = 1.646, 95%CI: 1.158–2.340; P = 0.005, FDR_P = 0.018) and further for folic acid use (OR = 1.607, 95%CI: 1.117–2.314; P = 0.011, FDR_P = 0.018) under the additive model. Mothers carried the variant allele (CT + TT) had a significantly higher odds of CHD compared with non-carriers (CC) in the fully adjusted model (OR = 1.725, 95%CI: 1.081–2.754; P = 0.022, FDR_P = 0.044) under the dominant model. MTRR rs1801394 was associated with a significantly increased risk of neonata CHD in the crude analysis (OR = 1.588, 95%CI: 1.114–2.261; P = 0.010, FDR_P = 0.020), which remained robust after adjusting for maternal age (OR = 1.601, 95%CI: 1.118–2.291; P = 0.010, FDR_P = 0.020) and further for folic acid use (OR = 1.544, 95%CI: 1.065–2.237; P = 0.022, FDR_P = 0.044) under the additive model. Mothers with the TT genotype at rs1801133 of the MTHFR gene had significantly higher serum Hcy levels than those with the CC or CT genotypes, and with the GG genotype at rs1801394 of MTRR higher than those with the AA genotype. Hcy partially mediated the associations between maternal genotypes (rs1801133 and rs1801394) and neonatal CHD, with a Prop.Mediated of 24.7% and 23.8% respectively (both P < 0.05). Maternal polymorphisms in MTHFR rs1801133 and MTRR rs1801394 were significantly associated with increased risk of neonatal CHD in the Chinese Han population of southern Fujian. Maternal polymorphisms in MTHFR rs1801133 and MTRR rs1801394 were significantly associated with elevated maternal serum Hcy levels, and Hcy partially mediated the associations between maternal genotypes (rs1801133 and rs1801394) and neonatal CHD. This was an observational study. According to the International Committee of Medical Journal Editors (ICMJE), purely observational studies (in which the allocation of medical interventions is not under the investigator's discretion) do not require registration.