Study objective A place for clonidine has been suggested for many indications in perioperative medicine. The aim of this systematic review and these meta-analyses is to systematically, and quantitatively, evaluate these potential indications of clonidine. Design, setting, patients and interventions We selected and analyzed (qualitatively and, when possible, quantitatively) the available literature published on PubMed/Medline and on the Cochrane database. Inclusion criteria included: human randomized controlled trials involving adults who received perioperative systemic (oral, intramuscular, transdermal and intravenous) clonidine for every type of surgery. Measurements and main results We identified 775 trials and thereafter excluded 718 and analyzed 57 trials concerning, in total, 14,790 patients of whom 7408 received clonidine and 6836 received placebo. Most important results shows that, in qualitative and quantitative analyses, clonidine vs placebo reduces analgesics consumption in, respectively, (159 vs 154 patients: 24%, 95%CI[16%–32%]; p < 0.001), reduces nausea and vomiting (risk ratio, in 180 vs 181 patients: 0.35, 95%CI[0.25–0.51]; p < 0.001), improves hemodynamic stability (reduction of HR: 14.9 bpm, 95%CI[10.4–19.5]; p < 0.001; reduction of the MAP: 12.5 mm Hg, 95%CI[7.14–17.86]; p < 0.001); 1 min after tracheal intubation, in 67 vs 68 patients), prevents postoperative shivering (risk ratio, in 140 vs 140 patients: 0.17, 95%CI[0.10–0.29]; p < 0.001). On the other hand, clonidine does not have any influence on renal and cardiac outcomes (adverse events rates, in 5873 vs 5533 patients: 0.00, 95%CI[− 0.10–0.11]; p = 0.96) and does not prolong awakening time. Conclusions In conclusion, these systematic review and meta-analyses of 57 trials confirm that clonidine improves pain control, reduces PONV, improves hemodynamic and sympathetic stability, with no adverse consequences on renal function or awakening time, but does not influence cardiac outcome in the general population, after non-cardiac surgery. Nevertheless, given the high heterogeneity between the studies, this does not exclude different results in patient subgroups or specific procedures.