Background and aim: The sedative role of dexmedetomidine (DEX) in gastrointestinal endoscopic procedures is unclear, highlighting the need to compare DEX with conventional sedatives for a full evaluation. We performed this systematic review and meta-analysis to assess the efficacy and safety of sedation with DEX alone or in combination during gastrointestinal endoscopic procedures with a view to providing guidance for clinical application. Methods: The PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases were searched for randomized controlled trials from inception to July 1, 2022. Standardized mean difference and weighted mean difference with 95% confidence interval or pooled risk ratios with 95% CI was used for continuous outcomes or dichotomous outcomes, respectively, and a random-effect model was selected regardless of the significance of the heterogeneity. Results: Forty-one studies with 3,015 patients were assessed, of which 1,363 patients were in the DEX group and 1,652 patients were in the control (without DEX) group. We found that DEX administration decreased the risk of body movements or gagging, hypoxia, and cough, reduced the additional requirement for other sedatives, and increased the endoscopist satisfaction level, however, induction time, and risk of bradycardia, and without statistical differences in RSS score, patient satisfaction level, recovery time, hypotension, nausea, and vomiting. Conclusion: DEX may benefit patients undergoing gastrointestinal endoscopic procedures in some clinical outcomes, whilst some potential disadvantages also exist. Remarkably, DEX was non-inferior to midazolam and propofol in terms of sedation level. In conclusion, DEX is an alternative option for sedation in gastrointestinal endoscopic procedures.