The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. Sec6 is a subunit of the exocyst complex that participates in various cellular activities. Here, we demonstrate that Sec6 negatively regulates cGAS through the apoptosis pathway. Specifically, Sec6 suppresses the type I IFN (IFN-I) signaling response by directly targeting cGAS and promoting its degradation. Mechanistically, Sec6 facilitates caspase3 activation by regulating the intrinsic mitochondrial apoptosis pathway. Further research revealed that Sec6 promotes caspase3 activation, leading to cleavage of cGAS at D319. To clarify the mechanism underlying Sec6-mediated caspase3 activation, the proteomic sequencing analysis revealed that Sec6 promotes BoHV-1-induced apoptosis. Additionally, enrichment analysis revealed that Sec6 upregulates the apoptosis-associated p53 pathway. Further validation confirmed that Sec6 activates the intrinsic mitochondrial apoptosis pathway by promoting p53 phosphorylation, upregulating Bax protein expression, and activated caspase3. Following silencing of p53 or Bax, Sec6 no longer suppressed the BoHV-1-induced IFN-I signaling response. The study elucidates how Sec6 negatively regulates the BoHV-1-induced innate immune via the p53-Bax-caspase3 signaling axis. It uncovers a previously unrecognized role for Sec6 in the antiviral innate immune response and provides a novel target for controlling BoHV-1 infection.