Background Many patients report moderate to severe pain in the acute postoperative period. Enhanced recovery protocols recommend multimodal analgesics, but the optimal combination of these is unknown. Purpose The aim of this study was to synthesize the best available evidence about effectiveness of multimodal analgesics on pain after adult cardiac surgery. Methods A systematic review to determine the effect of multimodal postoperative analgesics is proposed (International Prospective Register of Systematic Reviews Registration CRD42022355834). Multiple databases including the Cochrane Library, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, American Psychological Association, the Education Resources Information Centre, the Excerpta Medica database, the Medical Literature Analysis and Retrieval System Online, Scopus, Web of Science, and clinical trials databases will be searched. Screening in Covidence and quality assessment will be conducted by 2 authors. A grading of recommendations, assessment, development, and evaluation summary of findings will be presented if meta-analysis is possible.