Objectives This meta-analysis aimed to test the association of angiotensin-converting enzyme (ACE) gene I/D polymorphism with asthma risk and circulating ACE changes. Methods Public literature retrieval, publication selection, and information extraction were completed independently by two investigators. Effect-size values are expressed as odds ratios (ORs) or standardized mean differences (SMDs) with a 95% confidence interval (95% CI). Results Nineteen studies (2,888 patients and 9,549 controls) fulfilled the eligibility criteria. Overall investigations demonstrated that ACE gene I/D polymorphism was significantly associated with asthma risk under allelic (OR, 95% CI: 1.26, 1.08 to 1.48), homozygous genotypic (1.50, 1.09 to 2.06), and recessive (1.53, 1.24 to 1.89) models with moderate heterogeneity (I-2 statistic: 64% to 79%). Subsidiary investigations recorded that race, matched status, asthma diagnosis, sample size, and age possibly accounted for the existence of significant heterogeneity. Relative to carriers with the II genotype, those with the DD genotype, ID genotype, and the combination of DD and ID genotypes had significantly higher concentrations of circulating ACE (WMD: 3.13, 2.07, and 2.83 U/L, respectively, p < 0.05). Adoption of Mendelian randomization analyses revealed that one unit increment in circulating ACE concentrations was found to be significantly associated with a 1.14-fold increased risk of asthma (95% CI: 1.02 to 4.24). Conclusion We provided strong meta-analytical evidence supporting the causal implication of high circulating ACE concentrations in the development of asthma.