Background and Objectives <p>Performing medical procedures on children can often be challenging because of the anxiety that these procedures may induce, the need for immobility that they may require, or age-related development capabilities. We assessed the effects of procedural sedation and analgesia drugs for anxiety management in children during medical procedures.</p> Methods <p>We searched PubMed Medline, Cochrane Library, American Academy of Pediatrics, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and references of eligible studies. We included parallel-arm randomized controlled trials comparing different active drugs of procedural sedation and analgesia in children undergoing diagnostic or therapeutic, painful or nonpainful procedures. Two authors independently screened titles/abstracts, reviewed full-texts, and extracted data related to study characteristics, methodology, participants, and results. Meta-analyses involved the Mantel–Haenszel random-effects approach.</p> Results <p>We included 98 studies (9161 children) in the qualitative analysis and 50 in the quantitative analysis. The probability of successful sedation rate was associated with dexmedetomidine versus midazolam alone (odds ratio [OR] 7.42, 95% confidence interval [CI] 4.08–13.48) and with midazolam and ketamine combined versus midazolam alone (OR 3.0, 95% CI 1.67–5.39). The probability of successful sedation rate was associated with dexmedetomidine 2 μg/kg versus 1 μg/kg (OR 5.21, 95% CI 1.90–14.27).</p> Conclusions <p>Dexmedetomidine, and the combination of midazolam and ketamine, seem interesting for sedating children during medical procedures.</p>