Introduction Due to the increased prevalence of chronic conditions, multimorbidity and an increased complexity of care, the burden on healthcare teams is high resulting in unmet needs of patients and their family and a high workload on healthcare professionals. To respond to these challenges, care models integrating nurse practitioners were introduced. Despite the proven benefits, implementation in Belgium is at an early stage. The aim of this study is to develop, implement and evaluate nurse practitioner roles in a Belgian university hospital. Insights into development and implementation processes can inform healthcare managers and policymakers for future (nationwide) implementation. Methods and analysis For the development, implementation and (process-)evaluation of nurse practitioner roles in three departments in a Belgian university hospital, a participatory action research approach involving interdisciplinary teams of healthcare professionals, healthcare managers and researchers will be used. To investigate the effectiveness at patient (eg, quality of care), healthcare providers (eg, team effectiveness) and organisational level (eg, utility) a longitudinal (matched controlled) pre–post mixed methods study will be set up. Quantitative data (surveys, data from electronic patient files, administrative files) will be analysed using SPSS V.28.0. Qualitative data will be collected throughout the whole process and will consist of the meetings, (focus group) interviews and field notes. All qualitative data will be analysed thematically both across-case and within-case. This study is designed and will be reported based on the Standard Protocol Items: Recommendations for Interventional Trials 2013 statement. Ethics and dissemination Ethical approval for all parts of this study was obtained from the Ethics Committee of the participating university hospital (February–August 2021). All participants throughout the study parts will receive written and verbal information and will be asked written consent. All data will be ...