Objectives: This study focuses on analyzing the impact of innovative human resource management practices (IHRMP) on knowledge worker burnout, and how organizational support and employee effort help explain this relationship in the context of the business services sector. To explore the problem, investigated whether IHRMP have a significant negative impact on employee burnout, and organizational support and employee effort mediate the negative impact of IHRMP on employee burnout. Material and Methods: A survey was conducted, collected using the computer assisted web interview method on 1000 knowledge workers employed at business services sector (BSS) organizations in Poland. The quantitative results obtained were analyzed using AMOS software to test the main statistical relationships and through structural equation modeling. Results: The study outlines direct and indirect mechanisms to counteract perceived burnout among knowledge workers. The article contributes to the understanding of how IHRMP reduce burnout among knowledge workers and highlights the central importance of organizational support and employee effort as mediating factors against burnout in the context of high-skill, high-intensity work. Conclusions: The expected results in terms of application provide a proposal of measures for managers’ consideration that can be implemented in the organization with a view to counteracting the incidence of burnout among BSS employees. Int J Occup Med Environ Health. 2024;37(2):220–33