IntroductionThe current manuscript presents a protocol for a systematic review and meta-analysis of the evidence regarding the determinants of responsiveness to multidisciplinary management of chronic pain, with pain intensity, pain-related interference, physical functioning and health-related quality of life as the main outcomes, with consideration to multiple secondary outcomes.Methods and analysisTo identify relevant studies, the Ovid MEDLINE, PubMed, Ovid PsycINFO, EBSCO CINAHL and Scopus databases will be searched for all studies exploring factors associated with responsiveness to multidisciplinary pain management from study inception to the present. Cohorts, case–control studies and randomised controlled trials will be included. Independent screening for eligible studies will be completed by a total of four researchers using defined criteria. Data extraction will be executed by two researchers. Study heterogeneity will be estimated using the I² index. A meta-analysis will be performed using random effects models. Publication bias will be evaluated by means of funnel plots and Egger’s test.Ethics and disseminationThe proposed study does not involve collection of primary data. Therefore, no ethical approval is required. The results of the systematic review and meta-analysis will be presented in a peer-reviewed journal and at conferences.PROSPERO registration numberCRD42021236424.