Abstract Background and Aims: Postoperative sleep disturbances are associated with delayed recovery and increased incidences of complications. This systematic review aims to determine the impact of perioperative pharmacological therapies on postoperative sleep quality in the hospital. Material and Methods: We searched MEDLINE, MEDLINE ePubs and In-Process Citations (Daily), Embase Classic + Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and PubMed for randomized controlled trials (RCTs) from inception to May 2022, with continued literature surveillance until August 2023. Studies included consisted of noncardiac surgical patients aged ≥18 years with postoperative sleep in the hospital. The primary outcome was improvement in postoperative sleep outcomes such as sleep quality, duration, efficiency, architecture, and insomnia ratings after pharmacological treatment. Additional outcomes included postoperative pain scores and opioid consumption. Results: The search strategy yielded 21 studies (n = 3276), and 18 reported improved sleep outcomes using eight validated sleep measurement tools. Eight of 10 studies using dexmedetomidine via patient-controlled analgesia or intravenous infusion reported better sleep quality versus controls. Opioids (nalbuphine, tramadol plus sufentanil), nonopioids (zolpidem, midazolam, pregabalin), propofol total intravenous anesthesia (TIVA), S-ketamine, and ropivacaine nerve blocks were superior to controls in enhancing postoperative sleep quality. Eleven studies (52%) which included the combination of dexmedetomidine with opioids reported concurrent improvements in postoperative pain and sleep. Dexmedetomidine also decreased postoperative opioid analgesia consumption. Conclusions: Evidence for the effects of perioperative pharmacological approaches on postoperative sleep are limited. High-quality RCTs of adequate power and methodology on the effects of pharmacology interventions on postoperative sleep are warranted.