Dengue virus (DENV) is a pathogen with a high impact in human health that replicates in a wide range of cells of the immune system. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response (IFN). Thus, DENV can inhibit type I IFN signaling (described by several groups), and type I IFN production (described by our group). We documented the inhibition of type I IFN production in human monocyte derived dendritic cells (MDDCs) with an otherwise strong cytokine and chemokine profile in those cells and that the NS2B3 protease complex of DENV functions as an antagonist of type I IFN production, and its proteolytic activity is necessary for this event. Here we identify the human adaptor molecule STING as a target of the NS2B3 protease complex and characterize the mechanism of inhibition of the type I IFN production in primary human MDDCs mediated by this viral factor. We also describe that DENV NS2B3 cannot degrade the mouse version of STING, a phenomenon that strictly restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice.