IntroductionThe COVID-19 pandemic has had a significant impact on the physical and mental functioning of healthcare professionals, especially those working on the ‘frontline’, and other hospital workers. At the onset of the crisis, various interventions were introduced to promote resilience and offer mental support to these professionals. However, it is unknown whether the interventions will meet the needs of professionals as the COVID-19 pandemic continues.The goal of this exploratory study is to gain insight in factors that protect the vitality and resilience of Dutch hospital employees during the so-called ‘second wave’ of the COVID-19 pandemic. This paper describes the study protocol.Methods and analysisThis exploratory study applies a mixed-methods design, using both quantitative and qualitative methods of data collection and analysis. The first part of the study (substudy I) consists of surveys among doctors and nurses in COVID-19 departments and non-COVID-19 departments, and other professionals in the hospital (ie, managers and homeworkers) in 2020 and 2021. The second part of the study (substudy II) consists of focus groups and interviews among professionals of the intensive care unit, COVID-19 departments and infection prevention units.Ethics and disseminationThe research protocol for this study has been approved by the Medical Ethics Committee (MEC-2020-0705). The outcomes of this study will be used to develop and implement interventions to support hospital employees maintaining their vitality and resilience during and after the COVID-19 pandemic. Employees with vitality experience less work-related stress and make a positive contribution to healthcare quality.