OBJECTIVE: To identify which drugs are effective at preventing delirium after surgery in adults over 60 years of age and estimate the effects on morbidity and mortality. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Embase, Medline, and Cochrane Library up to 4 March 2024. ELIGIBILITY CRITERIA: Randomised controlled trials with administration of one or more drugs for the prevention of delirium after surgery requiring general or regional anaesthesia that recruited participants at least 60 years old and used a validated delirium assessment tool to measure the outcome. Surgery under local anaesthesia only, preoperative mechanical ventilation, and studies of interventions to treat delirium were excluded. DATA EXTRACTION AND SYNTHESIS: Assessors masked to each other's decisions screened studies, extracted data, and assessed risk of bias and quality of evidence in duplicate by using the Cochrane risk of bias tool version 2 and the CINeMA tool. Bayesian arm based network meta-analysis was used to compare interventions. RESULTS: 158 trials were identified with 41 084 participants comparing 52 drug interventions. Seventeen trials were rated as being at high risk of bias. The overall risk of delirium after surgery was 14.5% (n=5957). Dexmedetomidine (odds ratio 0.46, 95% credible interval 0.36 to 0.57), corticosteroids (0.53, 0.31 to 0.87), melatonin receptor agonists (0.54, 0.34 to 0.85), parecoxib (0.34, 0.16 to 0.74), olanzapine (0.27, 0.07 to 0.94), and intranasal insulin (0.13, 0.04 to 0.34) were the most effective interventions at preventing delirium in trials not at high risk of bias. Only corticosteroids reduced the severity of delirium (mean difference -2.42 (95% credible interval -4.72 to -0.12) Memorial Delirium Assessment Scale points). Most interventions had no effect on length of stay, mortality, cognition, or quality of life. Hypotension and bradycardia were more common with dexmedetomidine, but postoperative nausea and vomiting were reduced. Postoperative infection rates were not increased by corticosteroids. CONCLUSIONS: Dexmedetomidine is effective in the prevention of postoperative delirium. This finding remains after exclusion of studies at high risk of bias. Corticosteroids, melatonin receptor agonists, parecoxib, intranasal insulin, and olanzapine have potential benefit, although evidence is of moderate to very low quality. Evidence synthesis in this area is complicated by inadequate trial registration practices and incomplete adoption of core outcome sets. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023488337.