Objectives To evaluate the impact of volatile anesthetic choice on clinically relevant outcomes of patients undergoing cardiac surgery. Methods Major databases were systematically searched for randomized controlled trials (RCTs) comparing volatile anesthetics (isoflurane versus sevoflurane) in cardiac surgery. Study-level characteristics, intraoperative events, and postoperative outcomes were extracted from the articles. Results Sixteen RCTs involving 961 patients were included in this meta-analysis. There were no significant differences between both anesthetics in terms of intensive care unit length of stay (SMD −0.07, 95% CI −0.38 to 0.24, P = 0.66), hospital length of stay (SMD 0.06, 95% CI −0.33 to 0.45, P = 0.76), time to extubation (SMD 0.29, 95% CI −0.08 to 0.65, P = 0.12), S100β (at the end of surgery: SMD 0.08, 95% CI −0.33 to 0.49, P = 0.71; 24 hours after surgery: SMD 0.21, 95% CI −0.23 to 0.65, P = 0.34), or troponin (at the end of surgery: SMD −1.13, 95% CI −2.39 to 0.13, P = 0.08; 24 hours after surgery: SMD 0.74, 95% CI −0.15 to 1.62, P = 0.10). CK-MB was shown to be significantly increased when using isoflurane instead of sevoflurane (SMD 2.16, 95% CI 0.57 to 3.74, P = 0.008). Conclusions The volatile anesthetic choice has no significant impact on postoperative outcomes of patients undergoing cardiac surgery.