Inadequate post-operative pain management can have significant impacts on patients' quality of life. Effective management of acute pain after surgery is important for early mobilization and discharge from hospital, patient satisfaction, and overall well-being. Utilizing multimodal analgesic strategies has become the mainstay of acute post-operative pain management. A comprehensive search was performed, assessing the published or otherwise publically available literature on different central nervous system (CNS) drugs [excluding opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen] and their uses to treat acute post-surgical pain. Included among the drugs evaluated in this review are anticonvulsants, N-methyl-D-aspartic acid (NMDA) agonists, local anesthetics, α2-agonists, cannabinoids, serotonin-noradrenaline reuptake inhibitors (SNRIs), and serotonin-noradrenaline-dopamine reuptake inhibitors (SNDRIs). Timing, dosing, routes of administration, as well as mechanisms of action are discussed for these CNS drugs.