Background: Despite an intensive focus on workers’ health during recent decades, the prevalence of work-related diseases remains unchanged in Denmark and internationally. Therefore, USA and Australian researchers have initiated new paradigms for integration of health promotion, prevention of work-related disease, and organization of work. Inspired by the Australian WorkHealth Improvement Network program (WIN), this paper describes the background, design, intervention methodologies, and evaluation methods of an Integrated Approach to Health, Wellbeing, and Productivity at Work (ITASPA) intervention aiming to prevent work-related injuries and diseases and promote the health, safety, and wellbeing of the worker. Methods: Using a stepped wedge design, worksites will be enrolled at baseline and offered the intervention starting at different times. Data will be collected at baseline, before the off-set of the intervention, and after each implementation period. The effect evaluation will be based on a mixed-methods approach. The qualitative data are based on semi-structured interviews and focus groups. The quantitative data consists of questionnaires, anthropometrics, and resting blood pressure and will be analyzed based on the intention-to-treat principle in linear mixed models with random slope and intercept. Discussion: Integrated interventions are shown to increase overall health and safety at worksites more effectively and rapidly than more narrowly focused programs. Still, previous integrated interventions are lacking successful implementation. In ITASPA, the effects of the intervention is tested in a strong scientific mixed-methods design. Thus, the ITASPA project contributes to the knowledge about what characterizes a best practice for the implementation of integrated worksite interventions. Trial registration: ITASPA is retrospectively registered in Clinicaltrials.gov on May 19, 2023 (NCT05866978).