Objective Through the statistical analysis of the actual detection results of Down's disease screening and the pregnancy outcome of follow-up in Zhuhai, the health economics evaluation was carried out. Methods The data of 31967 pregnant women who underwent serum screening (SS) and non-invasive prenatal testing (NIPT) during the same pregnancy in Zhuhai City from 2018 to 2021 were retrospectively analyzed. The cost-benefit analysis was conducted according to 5 different screening strategies. Results Among 31,967 pregnancies, 38 were Down syndrome babies (including 3 pregnant women aged over 35 years), with a Down syndrome incidence of 1/841. Serological screening detected 1,649 cases of high risk of T21, of which 21 were true positives, with a positive predictive value of 1.27% and a detection rate of 55.3%; NIPT screening detected 49 cases of high risk of T21, 38 cases of Down syndrome babies, with a positive predictive value of 77.55% and a detection rate of 100%. The total cost generated by calculation strategy 4 was the lowest, about 27.44 million yuan. Conclusion NIPT can be used as primary screening test instead of serological screening method in prenatal Down's screening for secondary prevention and control of birth defects, which has great social and economic benefits.