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Abstract Background A comprehensive assessment of combined modifiable risk factors in relation to infectious diseases among individuals with hypertension is lacking, and the potential mechanisms of these associations remain unclear. To investigate the prospective associations of a combination of lifestyle behaviors and cardiometabolic factors with the risk of infectious diseases among individuals with hypertension and to estimate whether and to what extent blood biomarkers mediate these associations. Methods This cohort study included 147,188 participants with hypertension and complete data on modifiable risk factors from the UK Biobank. Health score was constructed from eight modifiable risk factors, including four lifestyle behaviors (diet, physical activity, smoking, and sleep duration) and four cardiometabolic factors (body mass index, blood lipids, blood glucose, and blood pressure). Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the health score and infectious diseases. The mediation analysis was performed to assess the potential intermediation effects of blood biomarkers. Results Over a median follow-up of 12.5 years, 27,398 participants with infectious diseases were documented, with 960 respiratory infectious diseases and 7940 digestive infectious diseases. After adjusting for potential confounders, the HR (95% CI) for the highest versus the lowest quartile of health score was 0.64 (0.62, 0.66) for infectious diseases, 0.72 (0.60, 0.86) for respiratory infectious diseases, and 0.66 (0.62, 0.71) for digestive infectious diseases. Stratified factors including duration of hypertension did not modify the associations between the health score and infectious diseases. In addition, biomarkers including inflammation and renal function collectively explained 46.60% of the associations between the combined lifestyle factors and infectious disease risk among individuals with hypertension. Conclusions and relevance Ideal management of combined modifiable risk factors was associated with lower risks of infectious diseases and might produce profound changes in blood biomarkers among individuals with hypertension. Additionally, specific biomarkers appeared to serve as an intermediate between combined lifestyle factors and infectious diseases. These insights highlighted the important role of a combination of healthy lifestyle and favorable cardiometabolic status in reducing disease burden and facilitated the understanding of biological mechanisms underlying modifiable risk factors with infectious diseases.