Questionnaires on health-related quality of life (HRQoL) play a crucial role in managing patients by revealing insights into physical, psychological, lifestyle, and social factors affecting well-being. A methodological aspect that has not been adequately explored yet, and is of considerable potential, is causal discovery. This study explored causal discovery techniques within HRQoL, assessed various considerations for reliable estimation, and proposed means for interpreting outcomes. Five causal structure learning algorithms were employed to examine different aspects in structure estimation based on simulated data derived from HRQoL-related directed acyclic graphs. The performance of the algorithms was assessed based on various measures related to the differences between the true and estimated structures. Moreover, the Resource Description Framework was adopted to represent the responses to the HRQoL questionnaires and the detected cause–effect relationships among the questions, resulting in semantic knowledge graphs which are structured representations of interconnected information. It was found that the structure estimation was impacted negatively by the structure’s complexity and favorably by increasing the sample size. The performance of the algorithms over increasing sample size exhibited a similar pattern, with distinct differences being observed for small samples. This study illustrates the dynamics of causal discovery in HRQoL-related research, highlights aspects that should be addressed in estimation, and fosters the shareability and interoperability of the output based on globally established standards. Thus, it provides critical insights in this context, further promoting the critical role of HRQoL questionnaires in advancing patient-centered care and management.