Working life is characterised by various requirements and degrees of control in meeting these demands. The imbalance of these elements with workers’ resources can result in work-related stress involving the repeated activation of stress response systems. Modifications in the bio-molecular profile may represent a biological signature of individuals’ life experiences and provide evidence on pathways through which such stressors can result in health outcomes. The aim of our systematic review is to characterize the quality of life (QOL) and the bio-molecular profile in the working population, to highlight if the alteration observed might be related to the working conditions. The article query was performed on PubMed, Embase, and Cochrane CENTRAL and results have been presented according to three molecular pathways involved in the stress response: oxidative stress, inflammation, and neuroendocrine activation. The epidemiological sample has been sub-grouped into “clinical” and “non-clinical” populations according to the presence of a diagnosis of psychological disorders. Besides some critical issues, the review highlights the importance of developing a valid array of biological indicators, measurable in non-invasive matrices, sensitive to both derangements from physiological conditions and stress reduction, useful for identifying those groups at higher risk of health outcomes and, eventually, promoting workers’ wellbeing.