Background: The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between Dexmedetomidine and Midazolam in many clinical randomized controlled trials (RCTs) were inconsistent and suspicious. We aimed to comprehensively evaluate the safety and efficacy between Dexmedetomidine and Midazolam for intraoperative sedation in the elderly via meta-analysis and systematic reviews.Methods: RCTs regarding to the comparison of sedative effects and safety between Dexmedetomidine and Midazolam in elderly patients (aged ≥ 60 years) will be comprehensively searched from 2000.10 to 2021.05 through 4 English databases and 4 Chinese databases. After extraction in duplicate, the systematic review and meta-analysis will be performed on the primary outcomes (hemodynamic changes, sedative effect, cognitive function) and secondary outcomes (analgesic effect, surgical characteristics, complications or adverse reactions) for assessing the two therapy methods using Review manage software (Version 5.3). Sensitivity analysis will be conducted to evaluate the heterogeneity of the results, funnel plot and Egger’s test will be performed to analyze publication bias of the included studies, and test sequential analysis will be applied to assess the robustness and reliability of preliminary meta-analysis results. Finally, rating quality of evidence and strength of recommendations on the meta results will be summarized by rating quality of evidence and strength of recommendations (GRADE) approach. Discussion: This systematic review and meta-analysis will evaluate the safety and efficacy between Dexmedetomidine and Midazolam for intraoperative sedation in the elderly, it will give an insight on the application of Dexmedetomidine and Midazolam, and will provide evidences-based reference for clinical decision makings.Systematic review registration: PROSPERO (CRD42021221897).