Fortification of staple grains with folic acid (FA) has been mandated in 73 countries as of 2025. We conducted a systematic review and meta-analysis of population-based studies that evaluated the association between mandatory FA fortification of wheat flour, maize flour, and/or rice and prevalence of critical congenital heart defects (CHDs), neural tube defects (NTDs) and their 3 subtypes, and orofacial clefts (OFCs) and their 2 subtypes, pre- and post-fortification with FA. We searched PubMed and Embase from inception to October 2021, screened records in duplicate, and extracted data using a standardized form. We estimated pooled prevalence odds ratios (ORs) and 95% confidence intervals (CI) using random-effects models. A total of 26 studies across 9 countries met our inclusion criteria. Five studies reported on any critical CHDs, 18 on NTDs or their subtypes, and 11 on OFCs or their subtypes. We found a non-significant 4% reduction in the odds of any critical CHDs following mandatory FA fortification (OR: 0.96, 95% CI: 0.92, 1.01). A strong protective association was noted for total NTDs (OR: 0.64; 95% CI: 0.57, 0.72), spina bifida (OR: 0.63; 95% CI: 0.53, 0.74), anencephaly (OR: 0.59; 95% CI: 0.51, 0.69), and encephalocele (OR: 0.63; 95% CI: 0.46, 0.85). Associations for total OFCs (OR: 0.90; 95% CI: 0.80, 1.00) and cleft palate (CP) (OR: 1.01; 95% CI: 0.85, 1.20) were non-significant. A protective effect of mandatory FA fortification was found for cleft lip with or without cleft palate (CL/CLP) (OR: 0.93; 95% CI: 0.89, 0.97). Consistent with previous literature, our findings support mandatory FA fortification as an effective population-level strategy to reduce NTDs. Meta-analyses of critical CHDs and OFCs were limited by fewer studies and should be further studied in the future.