The recognition of pathogen-derived nucleic acids is a critical mechanism by which the innate immune system detects viral infection. Upon activation, nucleic acid sensors initiate the expression of type I interferons and other inflammatory mediators, subsequently leading to potent antiviral immune responses. However, erroneous detection of nucleic acids can have deleterious consequences for the host by inducing the development of certain autoinflammatory disorders. Inappropriate sensing of self- nucleic acids underlies a spectrum of monogenic disease referred to as type interferonopathies, including the Aicardi-Goutières syndrome (AGS). These disorders are often driven by mutations in genes encoding for components of nucleic acid recognition pathways, thereby resulting in the constitutive activation of type I interferon responses. Insight into the molecular pathology of AGS has highlighted promising new targets that may be harnessed for the development of novel therapeutics to counter this disorder. Stimulator of interferon genes (STING) - a central adaptor of the cytosolic DNA sensing pathway - has been strongly implicated in the pathogenesis of distinct inflammatory disorders, including AGS. Therefore, pharmacological inhibition of STING presents a promising approach for the development of potent treatment strategies against these and potentially other STING-mediated, autoinflammatory diseases. Performing a cell-based small-molecule screen, we identified and characterized two series of compounds, which potently and selectively inhibit STING through a mechanism that blocks the activation-induced palmitoylation of STING. The identified small-molecules mediate this inhibition through covalent binding to a transmembrane predicted cysteine residue (Cys91) - a palmitoylation site required for STING activation. Using the inhibitors, we show that the palmitoylation of STING mediates the formation of multimeric complexes at the Golgi and the subsequent recruitment and activation of the direct downstream kinase TBK1. We also provide evidence that representatives of both identified compound classes potently inhibit STING-induced expression of inflammatory cytokines including type I interferon, in human and mouse cells. Furthermore, we also demonstrate that the identified STING inhibitors attenuate autoinflammatory disease features in a mouse model of AGS. Taken together, this work uncovers a small-molecule mediated mechanism to inhibit STING and demonstrates the pharmacological potential of targeting STING for the treatment of type I interferon driven disease such as AGS.