Natural gas drilling may pose multiple health risks, including congenital anomalies, through air pollutant emissions and contaminated water. Two recent studies have evaluated the relationship between natural gas activity and congenital anomalies, with both observing a positive relationship. We aimed to evaluate whether residence near natural gas wells is associated with critical congenital heart defects (CCHD), neural tube defects (NTD), and oral clefts in Oklahoma, the third highest natural gas producing state in the US. We conducted a retrospective cohort study among singleton births in Oklahoma (n = 476,600) to evaluate natural gas activity and congenital anomalies. We calculated an inverse distance-squared weighted (IDW) score based on the number of actively producing wells within a two-mile radius of the maternal residence during the month of delivery. We used modified Poisson regression with robust error variance to estimate prevalence proportion ratios (PPR) and 95% confidence intervals (CI) for the association between tertiles of natural gas activity (compared to no wells) and CCHD, NTD, and oral clefts adjusted for maternal education. We observed an increased, though imprecise, prevalence of NTDs among children with natural gas activity compared to children with no wells (2nd tertile PPR: 1.34, 95% CI: 0.93, 1.93; 3rd tertile PPR: 1.20, 95% CI: 0.82, 1.75). We observed no association with CCHD or oral clefts overall. Specific CCHDs of common truncus, transposition of the great arteries, pulmonary valve atresia and stenosis, tricuspid valve atresia and stenosis, interrupted aortic arch, and total anomalous pulmonary venous connection were increased among those living in areas with natural gas activity compared to those living in areas without activity, though not statistically significant. Our results were similar to previous studies for NTDs and specific CCHDs. Future directions include evaluating the association between specific phases of the drilling process and congenital anomalies to better refine the relevant exposure period.