Changing global wildfire landscapes necessitate exploration of the effects of exposure to wildfire smoke on health and disease. Exposure to this toxicant is not only associated with acute cardiopulmonary dysfunction, but is increasingly recognized as a serious risk factor for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the cellular and molecular mechanisms which underlie this association are not well understood. One potential mechanism linking neurotoxic environmental exposures with neurodegeneration is glial-mediated neuroinflammation, which may be influenced by innate immune signaling through the cGAS-STING pathway in response to damaged or mislocalized DNA. To address this hypothesis, we here exposed primary astrocyte-enriched mixed glial cultures to laboratory generated wildfire smoke particulate matter extract and subsequently examined their reactivity and inflammatory signaling by applying cutting-edge techniques in high content microscopy, deep learning-based image analysis, and transcriptomics. We found that wildfire smoke exposure elicits DNA damage and results in STING signal transduction in astrocytes, including the production and release of inflammatory cytokines, as well as STING-dependent neurotoxicity. To better understand the mechanisms underlying this phenomenon, we integrated transcriptomic data from in vitro and in vivo wildfire smoke exposures studies, which revealed central hubs for functional enrichment surrounding interferon signaling. Together, these data strongly identify STING signaling as a central modulator of astrocyte-mediated inflammation resulting from wildfire smoke exposure.