The paper aims to present the latest results of the study on the issue of work stress and the quality of work life (QWL) of entrepreneurs. The study introduced a novel examination of the relationship between work stress and the QWL specifically for entrepreneurs in Slovakia in an era of uncertain economic and business environment, a topic that is often underexplored in existing literature. The novelty of the study lies in the application of the QWL methodology to the entrepreneurial environment in Slovakia. The research aim was to analyze the relationship between workload and work frustration in the context of the quality of work life (QWL) of entrepreneurs and to identify key factors influencing work stress. Based on the analysis of data obtained from a large sample of 996 respondents through the QWL questionnaire collected in the period from 01/2024 to 03/2024, the study identifies key factors such as workload and work frustration that contribute to the perception of work stress. Using exploratory factor analysis and confirmatory factor analysis, we found out that there is a significant relationship between these factors. The results revealed that improving the quality of working life is essential for maintaining entrepreneurs’ satisfaction and added to the research novelty by providing empirical evidence on the importance of improving work-life quality to sustain entrepreneur satisfaction amidst constant changes and challenges in an uncertain entrepreneurial environment.