MicroRNAs (miRNAs), small non‐coding RNA molecules that post‐transcriptionally regulate gene expression, are known to play key roles in regulating immune responses and autoimmunity. We investigated miR‐146a expression in Sjögren's syndrome (SjS) patients as well as in the SjS‐prone C57BL/6.NOD‐Aec1Aec2 mouse model, to elucidate its involvement in SjS pathogenesis. Expression of miR‐146a was examined in the PBMCs of 25 SjS patients and ten healthy donors, as well as in PBMCs, salivary and lacrimal glands of SjS‐prone mice and WT C57BL/6J mice. Functional assays using THP‐1 human monocytes were conducted to determine the biological roles of miR‐146a in innate immunity. Expression of miR‐146a was significantly increased in SjS patients compared with healthy controls, and was upregulated in the salivary glands and PBMCs of the SjS‐prone mouse at both 8 wk (prior to disease onset) and 20 wk (full‐blown disease) of age. More importantly, functional analysis revealed roles for miR‐146a in increasing phagocytic activity and suppressing inflammatory cytokine production while migration, nitric oxide production and expression of antigen‐presenting/costimulatory molecules are not affected in human monocytic THP‐1 cells. Taken together, our data suggest that abnormal expression/regulation of microRNAs in innate immunity may contribute to, or be indicative of, the initiation and progression of SjS.