Background: We found microRNA (miR)-1246 to be significantly differentially expressed between severe active alopecia areata (AA) patients and healthy individuals. Objective: To explore the role and mechanism of miR-1246 in severe AA. Methods: Expression of miR-1246, dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A), and nuclear factor of activated T cells 1c (NFATc1) in peripheral CD4⁺ T cells and in scalp tissues of patients were detected using RT-qPCR, Western blot, and immunohistochemistry assays. Peripheral CD4⁺ T cells from the AA patients were transfected with lentiviral vectors overexpressing miR-1246. RT-qPCR and Western blot analysis were used to measure mRNA or protein expression of retinoic-acid-receptor-related orphan nuclear receptor gamma (ROR-γt), interleukin (IL)-17, DYRK1A, NFATc1, and phosphorylated NFATc1. Flow cytometry was used to assay the CD4⁺IL-17⁺ cells proportion. ELISA was used to measure cytokine levels. Results: miR-1246 levels decreased and DYRK1A and NFATc1 mRNA levels significantly increased in the peripheral CD4⁺ T cells and scalp tissues of severe active AA samples. NFATc1 protein expression was also significantly increased in the peripheral CD4⁺ T cells but not in the scalp tissues. NFATc1 positive cells were mainly distributed among infiltrating inflammatory cells around hair follicles. In peripheral CD4⁺ T cells of severe active AA, overexpression of miR-1246 resulted in significant downregulation of DYRK1A, NFATc1, ROR-γt, and IL-17 mRNA and phosphorylated NFATc1 protein, as well as a decrease in the CD4⁺IL-17⁺ cells proportion and the IL-17F level. Conclusion: miR-1246 can inhibit NFAT signaling and Th17 cell activation, which may be beneficial in the severe AA treatment.