BackgroundNoise and air pollution are significant environmental threats with proven adverse health effects. However, the causality between these ambient exposures and disease is still largely unknown. This study aims to provide genetic evidence for this gap and investigates the dual role of inflammatory factors, emphasizing the need for integrated public health strategies. MethodsWe included noise and air pollution as exposures, 91 inflammatory factors as mediators, and 26 diseases as outcomes. We explored causal relationships using Mendelian randomization. To ensure the reliability, we screened single nucleotide polymorphisms (SNPs) closely associated with exposure as instrumental variables (IVs), and assessed the pleiotropy and heterogeneity of these IVs. ResultsOur results suggest that “Hearing difficulty/problems with background noise” increases the risk of hypertension, bronchitis, and menopause; loud music exposure frequency increases the risk of bronchitis; noisy workplace raises the risk of hypertension, coronary heart disease, narcolepsy, and irritable bowel syndrome; NO2 increases the risk of myocardial infarction and chronic heart failure; NOx increases the risk of pneumonia and inflammatory diseases of female pelvic organs; and PM10 increases the risk of myocardial infarction, narcolepsy, and type 2 diabetes; PM2.5–10 increases the risk of developing pneumonia and type 2 diabetes. Furthermore, we found that nine inflammatory factors play a mediating role, of which four play a mediating role in increasing the risk of morbidity and eight play a mediating role in protection against ambient exposures. Finally, we selected SNPs significantly associated with exposure and outcome for enrichment analysis. ConclusionsThis study provides the first genetic evidence linking noise and air pollution to various diseases, highlighting the dual mediating role of inflammatory factors. Our findings align with the “One Health” framework, emphasizing the interconnectedness of environmental and human health. Integrated public health strategies considering these complex biological responses are essential for promoting overall well-being.