This study aims to investigate the relationship between serum folate levels and the risk of psoriasis by integrating observational study with Mendelian Randomization (MR) analysis.We firstly conducted an observational study using data from the National Health and Nutrition Examination Survey (NHANES). Subsequently, genetic instruments were selected for two-sample MR analyses to investigate the causal relationship between serum folate levels and the risk of psoriasis. The observational study showed no significant association between serum folate levels and psoriasis. In the fully adjusted model: serum folate as a continuous variable (OR = 0.99, 95% CI: 0.98 to 1.00, P = 0.071); serum folate quartiles Q4 vs Q1 (OR = 0.83, 95% CI: 0.58 to 1.19, P = 0.309). The MR analysis revealed that higher genetically predicted serum folate levels from Icelandic and Danish populations was significantly associated with a reduced risk of psoriasis (OR = 0.63, 95% CI, 0.45 to 0.88, P = 0.005). Similarly, higher genetically predicted serum folate levels from South Asian populations were also significantly associated with a lower risk of psoriasis (OR = 0.84, 95% CI, 0.72 to 0.98, P = 0.025). Integrating observational study with MR analysis suggests that serum folate levels are protective factors against psoriasis, indicating that higher serum folate levels may help prevent the onset of the disease.