The clinical significance of periconceptional folic acid supplementation (FAS) in the prevention of neonatal neural tube defects (NTDs) has been recognized for decades. Epidemiological data and experimental findings have consistently been indicating an association between folate deficiency in the first trimester of pregnancy and poor fetal development as well as offspring health (i.e., NTDs, isolated orofacial clefts, neurodevelopmental disorders). Moreover, compelling evidence has suggested adverse effects of folate overload during perinatal period on offspring health (i.e., immune diseases, autism, lipid disorders). In addition to several single-nucleotide polymorphisms (SNPs) in genes related to folate one-carbon metabolism (FOCM), folate concentrations in maternal serum/plasma/red blood cells must be considered when counseling FAS. Epigenetic information encoded by 5-methylcytosines (5mC) plays a critical role in fetal development and offspring health. S-adenosylmethionine (SAM), a methyl donor for 5mC, could be derived from FOCM. As such, folic acid plays a double-edged sword role in offspring health via mediating DNA methylation. However, the underlying epigenetic mechanism is still largely unclear. In this review, we summarized the link across DNA methylation, maternal FAS, and offspring health to provide more evidence for clinical guidance in terms of precise FAS dosage and time point. Future studies are, therefore, required to set up the reference intervals of folate concentrations at different trimesters of pregnancy for different populations and to clarify the epigenetic mechanism for specific offspring diseases.