BACKGROUND: Lifestyle scores have emerged as a practical tool to assess the risk of major non-communicable diseases (NCDs). However, most of them are primarily developed for single NCDs. Given the common risk factors for some of the major NCDs, we conducted a systematic review to evaluate the potential of existing lifestyle scores in predicting the risk of multiple NCD-related endpoints. METHODS: PubMed, Web of Science, the Cochrane Library, Embase, and Google Scholar were searched from inception to October 2024. We included observational studies assessing the association between lifestyle scores and the risk of morbidity or mortality of multiple NCDs, including type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer. RESULTS: Of 16,138 unique records identified by the search, 56 eligible studies were included in the systematic review, consisting of 48 cohort studies, 5 case-control studies, 2 case-cohort studies, and 1 cross-sectional study from 16 countries. 15 lifestyle scores were identified to estimate the risk of 32 NCDs, with HLI CONCLUSION: All 15 simple lifestyle scores were shown to estimate the risk of multiple NCDs endpoints, although some scores were originally developed to estimate the risk of single diseases only. Therefore, further research is required to identify which lifestyle score is most effective for assessing the risk of multiple NCD-related endpoints in a head-to-head comparison.