Esmolol has been shown to improve postoperative pain and reduce opioid requirements. The aim of this systematic review was to evaluate the effect of perioperative esmolol as an adjunct on early postoperative pain intensity, recovery profile, and anesthetic requirement. Databases were searched for randomized placebo-controlled trials evaluating the effects of esmolol during general anesthesia. Primary outcomes were related to early postoperative pain whereas secondary outcomes were related to emergence time, postoperative nausea and vomiting, and intraoperative anesthetic requirement. Nineteen trials were identified involving 936 patients (esmolol = 470, placebo = 466). In esmolol group, numeric pain scores at rest in the immediate postoperative period were reduced by 1.16 (95% confidence interval [CI]: 1.97–0.35, I2 = 96.7%) out of 10. Opioid consumption was also decreased in the postanesthesia care unit compared with placebo, mean difference of 5.1 mg (95% CI: 7.0–3.2, I2 = 96.9%) morphine IV equivalents; a 69% reduction in opioid rescue dosing was noted (odds ratio [OR]: 0.31, 95% CI: 0.16–0.80, I2 = 0.0%). A 61% reduction in postoperative nausea and vomiting was also evident (OR: 0.39, 95% CI: 0.20–0.75, I2 = 60.7%). A reduction in propofol induction dose was noted in the esmolol group (mean difference: −0.53 mg/kg, 95% CI: −0.63–−0.44, I2 = 0.0%). A decrease in end-tidal desflurane equivalent (mean difference: 1.70%, 95% CI: −2.39–−1.02, I2 = 92.0%) and intraoperative opioid usage (fentanyl equivalent, mean difference: 440 μg, 95% CI: −637–−244, I2 = 99.6%) was observed in esmolol group. Esmolol had no effect on the emergence time. Perioperative esmolol as an adjunct may reduce postoperative pain intensity, opioid consumption, and postoperative nausea vomiting. Given the heterogeneity, larger clinical trials are warranted to confirm these findings.