PURPOSE: To date, no study has demonstrated the role of transdermal 17β-estradiol + norethisterone acetate on all of the risk factors for cardiovascular disease in postmenopausal women. To overcome this knowledge gap, a systematic review and meta-analysis were conducted to determine the effects of this combination treatment on BMI, body weight, waist/hip ratio, fibrinogen, factor VII, lipoprotein(a), fasting blood sugar, insulin, HbA, TG, LDL-C, HDL-C, and TC in postmenopausal women. METHODS: PubMed/Medline, SCOPUS, Web of Science, Embase, and Google Scholar were searched for relevant articles published between the inception of each database and April 6, 2023. The sample size and mean (SD) were used to calculate overall effect size using a random-effects model. FINDINGS: A total of 10 articles with 14 arms were included in the meta-analysis. On pooled analysis of effect size, fibrinogen (weighted mean difference [WMD], -0.18 g/L; 95% CI, -0.25 to -0.10), factor VII (WMD, -9.58; 95% CI, -12.51 to -6.64), LDL-C (WMD, -13.09 mg/dL; 95% CI, -18.48 to -7.71), and TC (WMD, -12.61 mg/dL; 95% CI, -18.11 to -7.12) were significantly affected with the use of transdermal 17β-estradiol + norethisterone acetate (all, P < 0.001), but effects on lipoprotein(a), TG, HDL-C, fasting blood sugar, insulin, HbA, BMI, body weight, and waist/hip ratio were not significant. IMPLICATIONS: Based on the findings from the present systematic review and meta-analysis, it was concluded that transdermal administration of 17β-estradiol + norethisterone acetate had beneficial impacts on fibrinogen, factor VII, LDL-C, and TC, suggesting a possible application in the reduction of cardiovascular disease risk.