Several studies suggest beneficial effects of perioperative statin therapy on postoperative outcome after cardiac surgery. However, recent randomized controlled trials (RCTs) show potential detrimental effects. The objective of this systematic review is to examine the association between perioperative statin therapy and clinical outcomes in cardiac surgery patients. Electronic databases were searched up to 1 November 2016 for RCTs of preoperative statin therapy versus placebo or no treatment in adult cardiac surgery. Postoperative outcomes were acute kidney injury, atrial fibrillation, myocardial infarction, stroke, infections, and mortality. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using fixed-effects meta-analyses. Primary analysis was restricted to trials with low risk of bias according to Cochrane methodology, and sensitivity analyses examined whether the risk of bias of included studies was associated with different results. We performed trial sequential analysis (TSA) to test the strength of the results. We included data from 23 RCTs involving 5102 patients. Meta-analysis of trials with low risk of bias showed that statin therapy was associated with an increase in acute kidney injury (314 of 1318 (23.82%) with statins versus 262 of 1319 (19.86%) with placebo; OR 1.26 (95%CI 1.05 to 1.52); p = 0.01); these results were supported by TSA. No difference in postoperative atrial fibrillation, myocardial infarction, stroke, infections, or mortality was present. On sensitivity analysis, statin therapy was associated with a slight increase in hospital mortality. Meta-analysis including also trials with high or unclear risk of bias showed no beneficial effects of statin therapy on any postoperative outcomes. There is no evidence that statin therapy in the days prior to cardiac surgery is beneficial for patients’ outcomes. Particularly, statins are not protective against postoperative atrial fibrillation, myocardial infarction, stroke, or infections. Statins are associated with a possible increased risk of acute kidney injury and a detrimental effect on hospital survival could not be excluded. Future RCTs should further evaluate the safety profile of this therapy in relation to patients’ outcomes and assess the more appropriate time point for discontinuation of statins before cardiac surgery.