Complement activation modulates DC-mediated T-cell activation, but whether complement affects DC-mediated priming of NK cells is unknown. Here, we demonstrated that conventional DCs (cDCs) from C3−/− and C5aR−/− mice are hyperresponsive to polyI:C, a TLR3 ligand, leading to enhanced NK-cell activation. We found that cDCs lack C5a receptor (C5aR) and do not respond to C5a directly. Depletion of Gr-1+ myeloid cells augments polyI:C-induced cDC activation in WT but not in C3−/− or C5aR−/− mice, indicating that the effect of complement activation on cDCs is indirectly mediated through C5aR-expressing Gr-1+ myeloid cells. We further demonstrated that the mechanism by which Gr-1+ myeloid cells regulate the activity of cDCs involves C5a-dependent TGF-β1 production in Gr-1+ myeloid cells. C5a enhances and blocking C5aR decreases TGF-β1 production in cultured bone marrow Gr-1+CD11b+ cells. C5aR deficiency is associated with reduced circulating TGF-β1 levels, while depleting Gr-1+ myeloid cells abrogates this difference between WT and C5aR−/− mice. Lastly, we showed that enhanced cDC–NK-cell activity in C3−/− mice led to delayed melanoma tumor growth. Thus, complement activation indirectly regulates cDC–NK-cell activation in response to inflammatory stimuli such as TLR3 by promoting TGF-β1 production in Gr-1+ myeloid cells at steady state.