AIM: To comprehensively assess the relationship between asthma and myopia based on the National Health and Nutrition Examination Survey (NHANES) database combined with Mendelian randomization (MR). METHODS: Initially, 20 497 subjects from the complete questionnaire cycle in the NHANES database from 2005 to 2008 were included. By exclusion criteria, 8460 subjects were screened with 1676 myopia samples and 6784 control samples. Subsequently, baseline characteristics, association analyses, risk stratification analyses, and receive operating characteristic curve (ROC) were used to investigate the associations between covariates and myopia. Then, the causal relationship was explored in depth by MR analysis, and was estimated the reliability by sensitivity analyses and directionality tests. RESULTS: Baseline characteristics illustrated a significant difference between myopia and controls for both asthma and covariates (excluding gender; P<0.05). The results in all three models indicated that asthma was strongly associated with myopia and the effect on myopia was not significantly confounded by other covariates [model 3: odd ratio (OR)=1.31; 95%CI=1.07-1.62; P=0.0133]. The risk stratification analysis again verified that asthma remained strongly associated with myopia and was a risk factor for myopia (P<0.05, OR>1). ROC proved that the model was accurate in its prediction [area under curve (AUC)=0.7]. Subsequently, the causal relationship between them was statistically significant (P<0.05) according to the inverse variance weighted (IVW) method in MR. Scatterplot showed that asthma and myopia had significant positive causality and were not affected by confounders. Forest plot displayed an increasing risk of myopia on asthma (OR>1). The funnel plot demonstrated compliance with Mendel’s second law. Sensitivity analysis and directional analysis further confirmed the confidence of the MR analysis results and a unidirectional causal relationship between them. CONCLUSION: A significant association and causality between asthma and myopia is found through the NHANES database and MR analysis, which is important implications for public health policy development and clinical practice.