Background: Chronic pelvic pain with various etiologies and mechanisms affects men and women and is a major challenge. Monotherapy is often unsuccessful for chronic pelvic pain, and combinations of different classes of medications are frequently prescribed, with the expectation of improved outcomes. Although a number of combination trials for chronic pelvic pain have been reported, we are not aware of any systematic reviews of the available evidence on combination drug therapy for chronic pelvic pain. Objective: We have developed a protocol for a systematic review to evaluate available evidence of the efficacy and safety of drug combinations for chronic pelvic pain. Methods: This systematic review will involve a detailed search of randomized controlled trials investigating drug combinations to treat chronic pelvic pain in adults. The databases searched will include the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from their inception until the date the searches are run to identify relevant studies. The primary outcome will be pain relief measured using validated scoring tools. Secondary outcomes, where reported, will include the following: adverse events, serious adverse events, sexual function, quality of life, and depression and anxiety. Methodological quality of each included study will be assessed using the Cochrane Risk of Bias Tool. Results: The systematic review defined by this protocol is expected to synthesize available good quality evidence on combination drug therapy in chronic pelvic pain, which may help guide future research and treatment choices for patients and their health care providers. Conclusions: This review will provide a clearer understanding of the efficacy and safety of combination pharmacological therapy for chronic pelvic pain.