Introduction In the pandemic, healthcare professionals face even higher levels of stress. It is therefore a priority to estimate the impact of the pandemic on mental health and to propose targeted strategies to improve resilience. The aims of the study were to (1) assess the mental health of healthcare professionals working with patients with COVID-19 and identify social determinants that may increase the risk of negative outcomes; and (2) test the effectiveness of an intervention to improve the resilience of healthcare professionals in France. Methods and analysis To evaluate the first objective, a national longitudinal study will be carried out among healthcare professionals working with patients with COVID-19. Participants will be recruited via an internet link that will be widely disseminated on social media, mailing lists, medical boards and French medical journals. Primary outcomes are mental health distress/symptoms and resilience. Secondary outcomes are burnout, social and occupational supports and substance use. To meet the second objective, an interventional study will be conducted. The main outcome is the effectiveness of the PsySTART-Responder and the Anticipate.Plan.Deter program. Qualitative analyses will be conducted to understand the strategies used to cope with the pandemic. Ethics and dissemination The study protocol was approved by the Sorbonne Université Ethical Committee (No 2020-CER-2020-27) and was declared to French Commission on Information Technology and Liberties, CNIL (N°2222413, 20-05-2021). The results of this study will provide a better understanding of mental health and social inequalities in mental health among healthcare professionals working in the pandemic; data about the effectiveness of the PsySTART-Responder and the Anticipate.Plan.Deter interventional program in France.