BACKGROUND: Sleep macrostructure is commonly disturbed after surgery. Postoperative pain control remains challenging. Given the bidirectional interaction between sleep and pain, understanding the role of modulation of sleep during the perioperative period on postoperative pain is needed. METHODS: This was a systematic review. Controlled trials examining the effects of perioperative sleep-promoting pharmacological agents on postoperative pain and analgesic consumption were identified through a systematic search strategy utilizing multiple electronic databases. RESULTS: Fourteen studies (9 melatonin, 5 zolpidem) involving 921 patients (melatonin n = 586, zolpidem n = 335) were included. Compared to placebo, melatonin reduced postoperative pain scores by ≥30% and significantly decreased opioid consumption in 3 studies (postoperative day [POD] 1-2), whereas 4 studies reported no significant effect of melatonin on postoperative pain. Compared to placebo, zolpidem reduced postoperative pain scores during POD1-7/POD1-14 in 2 studies, but only 1 trial suggested clinically meaningful improvement (ie, relative reduction of pain score ≥ 30%). Whereas 3 zolpidem trials showed no significant differences regarding postoperative pain ratings, zolpidem treatment was associated with decreased analgesic consumption in 4 out of 5 trials. Several limitations of the included studies were identified; only 1 study out of 14 was deemed to be at low risk of bias, and heterogeneity of the study design and outcome assessment precluded meta-analysis. CONCLUSION: Perioperative addition of a sleep-promoting pharmacological agent may improve pain control, but underlying evidence is weak and results are inconsistent. Only 5 of the 14 studies objectively evaluated changes in sleep (polysomnography, 2 zolpidem studies; actigraphy, 3 melatonin studies), which complicates conclusions regarding links between perioperative sleep and pain.