Polygenic risk scores (PRSs) represent a promising innovation in the context of precision health, but their benefits for patients and healthcare systems remain unclear. This systematic review examined the methods used to quantify the costs and benefits of PRS-based approaches across different healthcare contexts, summarizing current evidence and identifying challenges. A systematic search of three databases was conducted, and full economic evaluations related to any intervention based on polygenic risk stratification strategies were included (PROSPERO CRD42023442780). Quality was assessed using the Quality of Health Economic Studies instrument. Studies were grouped into three categories (cancer, cardiovascular disease, and other diseases), and key methodological features and characteristics were extracted. A total of 24 cost-utility analyses of generally high quality were included: 16 studies focused on cancer, five on cardiovascular disease, and three on other diseases. Studies on cancer mainly aimed to optimize screening programs, while in the other fields, PRSs were mostly used to refine eligibility for preventive therapies. Analyses were robust, but they mostly relied on hypothetical cohorts, had limited generalizability, paid insufficient attention to implementation aspects-including the delivery model-and considered only clinical benefits. Despite a positive trend toward cost effectiveness following PRS implementation, several challenges remain. These include the limited use of real-world data, issues of representativeness, and gaps in accounting for implementation costs, as well as long-term health and non-health benefits. Further research and pilot studies are needed to evaluate both the costs and benefits of PRS applications across diverse populations for multiple health outcomes simultaneously.