Myeloid cells express a plethora of C‐type lectin receptors (CLRs) that can regulate immune responses. CLEC‐2 belongs to the Dectin‐1 sub‐family of CLRs that possess an extracellular C‐type lectin‐like domain and a single intracellular hemITAM motif. CLEC‐2 is highly expressed on mouse and human platelets where it signals via Syk to promote aggregation. We generated a monoclonal antibody (mAb) against mouse CLEC‐2 and found that CLEC‐2 is additionally widely expressed on leukocytes and that its expression is upregulated during inflammation. MAb‐mediated crosslinking of CLEC‐2 leads to hemITAM‐dependent signaling via Syk, Ca²⁺ and NFAT and, in myeloid cells, modulates the effect of toll‐like receptor (TLR) agonists to selectively potentiate production of IL‐10. A macrophage/dendritic cell‐dependent increase in IL‐10 is also observed in mice given anti‐CLEC‐2 mAb together with LPS. Collectively, these data indicate that CLEC‐2 is expressed in myeloid cells and acts as a Syk‐coupled CLR able to modulate TLR signaling and inflammatory responses.