Background: Collaborative care interventions have been proposed as a promising strategy to support patients with multimorbidity.Despite this, the effectiveness of collaborative care interventions requires further evaluation. Existing systematic reviews describingthe effectiveness of collaborative care interventions in multimorbidity management tend to focus on specific interventions, patientsubgroups, and settings. This necessitates a comprehensive review that will provide an overview of the effectiveness of collaborativecare interventions for adult patients with multimorbidity. Objective: This systematic review aims to systematically assess the effectiveness of collaborative care interventions in comparisonto usual care concerning health-related quality of life (HRQoL), mental health, and mortality among adult patients withmultimorbidity. Methods: Randomized controlled trials evaluating collaborative care interventions designed for adult patients (18 years andolder) with multimorbidity compared with usual care will be considered for inclusion in this review. HRQoL will be the primaryoutcome. Mortality and mental health outcomes such as rating scales for anxiety and depression will serve as secondary outcomes.The systematic search will be conducted in the CENTRAL, PubMed, CINAHL, and Embase databases. Additional reference andcitation searches will be performed in Google Scholar, Web of Science, and Scopus. Data extraction will be comprehensive andinclude information about participant characteristics, study design, intervention details, and main outcomes. Included studies willbe assessed for limitations according to the Cochrane Risk of Bias tool. Meta-analysis will be conducted to estimate the pooledeffect size. Meta-regression or subgroup analysis will be undertaken to explore if certain factors can explain the variation in effect between studies, if feasible. The certainty of evidence will be evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results: The preliminary literature search was performed on February 16, 2024, and yielded 5255 unique records. A follow-up search will be performed across all databases before submission. The findings will be presented in forest plots, a summary of findings table, and in narrative format. This systematic review is expected to be completed by late 2024. Conclusions: This review will provide an overview of pooled estimates of treatment effects across HRQoL, mental health, andmortality from randomized controlled trials evaluating collaborative care interventions for adults with multimorbidity. Furthermore,the intention is to clarify the participant, intervention, or study characteristics that may influence the effect of the interventions.This review is expected to provide valuable insights for researchers, clinicians, and other decision-makers about the effectivenessof collaborative care interventions targeting adult patients with multimorbidity Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO) CRD42024512554;https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=512554 International Registered Report Identifier (IRRID): DERR1-10.2196/58296