INTRODUCTION: Unhealthy lifestyles caused a huge disease burden. Adopting healthy lifestyles is the most cost-effective strategy for preventing non-communicable diseases. The aim was to perform a systematic review and meta-analysis to quantify the relationship of combined lifestyle factors (eg, cigarette smoking, alcohol consumption, physical activity, diet and overweight/obesity) with the risk of all-cause mortality, cardiovascular mortality and incident cardiovascular disease (CVD). METHODS: PubMed and EMBASE were searched from inception to April 2019. Cohort studies investigating the association between the combination of at least three lifestyle factors and all-cause mortality, cardiovascular mortality or incidence of CVD were filtered by consensus among reviewers. Pairs of reviewers independently extracted data and evaluated study quality. Random-effects models were used to pool HRs. Heterogeneity and publication bias were tested. RESULTS: In total, 142 studies were included. Compared with the participants with the least-healthy lifestyles, those with the healthiest lifestyles had lower risks of all-cause mortality (HR=0.45, 95% CI 0.41 to 0.48, 74 studies with 2 584 766 participants), cardiovascular mortality (HR=0.42, 95% CI 0.37 to 0.46, 41 studies with 1 743 530 participants), incident CVD (HR=0.38, 95% CI 0.29 to 0.51, 22 studies with 754 894 participants) and multiple subtypes of CVDs (HRs ranging from 0.29 to 0.45). The associations were largely significant and consistent among individuals from different continents, racial groups and socioeconomic backgrounds. CONCLUSIONS: Given the great health benefits, comprehensively tackling multiple lifestyle risk factors should be the cornerstone for reducing the global disease burden.