The cleft lip and palate is a congenital malformation of multifactorial etiology, with high prevalence worldwide. Supplementation with folic acid could play an important role in the prevention and rescue of the expression of cleft lip with or without palatal involvement when it is consumed in preconception and early stages of pregnancy. The objective of this study was to evaluate the influence of the alteration of the folate pathway and folic acid supplementation on the incidence of non-syndromic cleft lip with or without cleft palate. A systematic review was carried out from 12 articles that correspond to primary studies between the years 2015 and 2021, retrieved from the EBSCO and PUBMED databases, subjected to pre-selection and selection stages through the application of inclusion and exclusion criteria. The alteration in the folate pathway could behave as a risk factor for cleft lip with or without palatal involvement (OR = 2.98; 95 % CI[1.5 - 5.9]; I2 = 43 %; p < 0.00001), while folic acid supplementation would behave as a protective factor (OR = 0.43; 95 % CI[0.3 - 0.6]; I2 = 86 %; p = 0.002). The studies indicate that folic acid could be relevant in the prevention and rescue of non-syndromic cleft lips with or without cleft palate. Due to the small sample size of the studies, the evidence remains limited.