INTRODUCTION: The aim of this systematic review was to evaluate the efficiency of different analgetic regimes used in clinical practice in reducing postoperative pain and cumulative opioid consumption following total knee arthroplasty (TKA). MATERIALS AND METHODS: A systematic search was conducted on PubMed, Embase and Scopus according to PRISMA guidelines in order to identify appropriate studies published between 2010 and 2025, which investigated different oral or intravenous analgesic strategies (duloxetine, acetaminophen, corticosteroids, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and gabapentinoids) in populations of patients receiving TKA by having as primary outcome the quantification of postoperative pain scores or opioid consumption. RESULTS: Out of the 1069 identified articles, 63 met the inclusion criteria. Duloxetine improved pain scores following TKA and reduced opioid consumption, however without reaching clinical relevance. Acetaminophen, despite moderate evidence for its efficiency, remains one of the most commonly used analgesics following TKA. Gabapentinoids are useful in reducing chronic neuropathic pain, but lack efficiency in the acute clinical setting. Opioids, although highly prescribed, fail to demonstrate a clinical benefit. Intravenous corticosteroids can also provide significant pain relief due to extensive anti-inflammatory properties, while NSAIDs remain one of the mainstays of treatment due to the relevant opioid-sparing effect and acceptable safety profile. CONCLUSIONS: The appropriate management of postoperative pain following TKA relies on a multimodal approach, which emphasizes the predominant use of non-opioid analgesics. NSAIDs and acetaminophen remain validated treatments, while the applicability of other alternative agents requires further exploration in large studies.