The endoplasmic reticulum (ER)-localized stimulator of interferon genes (STING) is the core adaptor for the pathogenic-DNA-triggered innate response. Aberrant activation of STING causes autoinflammatory and autoimmune diseases, raising the concern about how STING is finely tuned during innate response to pathogenic DNAs. Here, we report that the transmembrane domain (TM)-containing ER-localized E3 ubiquitin ligase TRIM13 (tripartite motif containing 13) is required for restraining inflammatory response to pathogenic DNAs. TRIM13 deficiency enhances pathogenic-DNA-triggered inflammatory cytokine production, inhibits DNA virus replication, and causes age-related autoinflammation. Mechanistically, TRIM13 interacts with STING via the TM and catalyzes Lys⁶-linked polyubiquitination of STING, leading to decelerated ER exit and accelerated ER-initiated degradation of STING. STING deficiency reverses the enhanced innate anti-DNA virus response in TRIM13 knockout mice. Our study delineates a potential strategy for controlling the homeostasis of STING by transmembrane ER-associated TRIM13 during the pathogenic-DNA-triggered inflammatory response.