Dengue virus (DENV) is the most prevalent mosquito borne virus, causing near to 400 million infections a year in more than 100 countries. In order to make a productive infection in humans, DENV actively inhibits the type I IFN system. Our group has reported that the virus encoded protease complex (NS2B3) cleave STING to avoid type I IFN production. To explore the sensors that collaborate with STING in DENV detection, we performed a systematic analysis of different pattern recognition receptors (PRRs) during infection. We report that the DNA sensor cGAS is involved in early detection of DENV infection, by detecting misplaced mitochondrial DNA in the cytoplasm of infected cells. Furthermore, the DENV NS2B protease co-factor specifically interacts with cGAS during infection and promotes its degradation in an autophagy-lysosome dependent mechanism. This degradation results in an inhibition of the cGAS/cGAMP/STING cytosolic DNA sensing pathway in primary human dendritic cells. Using biochemical and immunofluorescence techniques, we demonstrate a novel mechanism by which the DNA sensor cGAS detects cellular collateral damage during DENV infection.