BACKGROUND: Previous studies showed the conflicting associations between circulating micronutrient levels and systemic lupus erythematosus (SLE). Therefore, we aimed to clarify the causal association between circulating micronutrient levels and the risk of SLE by two-sample Mendelian randomization (MR) analysis. METHODS: 56 single nucleotide polymorphisms (SNPs) significantly associated with 14 circulating micronutrients (vitamin A, B6, B9, B12, C, D and E, phosphorus, calcium, magnesium, copper, iron, zinc, and selenium) in published genome-wide association studies (GWAS) were used as instrumental variables (IVs). And summary statistics related to SLE were obtained from the IEU OpenGWAS database. We used the MR Steiger test to estimate the possible causal direction between circulating micronutrients and SLE. In the MR analysis, inverse variance weighting (IVW) method and the Wald ratio was as the main methods., Moreover, the MR-Pleiotropy residuals and outliers method (MR-PRESSO), Cochrane's Q-test, MR-Egger intercept method and leave-one-out analyses were applied as sensitivity analyses. Additionally, we conducted a retrospective analysis involving the 20,045 participants from the Third National Health and Nutritional Examination Survey (NHANES III). Weight variables were provided in the NHANES data files. Univariate and multivariate logistic regression analyses were performed to determine the associations between circulating micronutrients and SLE. RESULTS: The MR estimates obtained from the IVW method revealed potential negative correlations between circulating calcium (OR: 0.06, 95% CI: 0.01-0.49, = 0.009), iron levels (OR: 0.63, 95% CI: 0.43-0.92, = 0.016) and the risk of SLE. The results remained robust, even under various pairs of sensitivity analyses. Our retrospective analysis demonstrated that the levels of vitamin D, serum total calcium, and serum iron were significantly lower in SLE patients ( = 40) when compared to the control group ( = 20,005). Multivariate logistic regression analysis further established that increased levels of vitamin D and serum total calcium served as protective factors against SLE. CONCLUSION: Our results provided genetic evidence supporting the potential protective role of increasing circulating calcium in the risk of SLE. Maintaining adequate levels of calcium may help reduce the risk of SLE.