To investigate how hormone replacement therapy (HRT) intervention affects cognitive function in randomized controlled trials of healthy postmenopausal women, the PubMed and Web of Science databases were searched for relevant publications up to 1 May 2020. Random-effects, subgroup analysis, sensitivity analysis and meta-regression analyses were conducted with 23 selected publications. HRT had a significant negative effect on global cognition (standardized mean difference (SMD): −0.04, 95% confidence interval (CI): −0.08 to −0.01). Via subgroup analysis, for those older than 60 years and with more than 6 months’ intervention duration, HRT aggravated global cognition (SMD: −0.05, 95% CI: −0.08 to −0.01; SMD: −0.05, 95% CI: −0.08 to −0.01). The results of meta-regression demonstrated no significant association between HRT intervention and global cognition after adjusting for participants’ age or intervention duration. In conclusion, HRT had a significant negative effect on global cognition, and this effect might be especially more visible for those aged more than 60 years and with more than 6 months’ intervention. Further randomized controlled trials for postmenopausal women with a younger age and short-term HRT exposure are necessary to clarify the effects of HRT on global and domain-specific cognitive functions.