Abstract The coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major ongoing pandemic, which results in life-threatening pneumonia and multiple-organ failure. Although the molecular mechanisms by which SARS-CoV-2 lead to various disease sequalae remain elusive, exaggerated inflammatory and immune responses can lead to the debilitating and lethal outcomes of this disease. Understanding how immune mechanisms contribute to the development of severe symptoms is essential for designing effective countermeasures against SARS-CoV-2. Our studies show that SARS-CoV-2 induces increased extracellular secretion of high-mobility group box 1 (HMGB1), a prominent damage-associated molecular pattern family member that alerts the immune system to potential damage and triggers immediate response. The goal of this study is to dissect the molecular mechanisms that promotes the release of HMGB1 and its associated cellular signaling in response to SARS-CoV-2 infection. Studies were conducted in human lung epithelial cells including A549-ACE2 and Calu-3/2B4 cells, mice, and COVID-19 patient samples. HMGB1 levels and oxidative stress markers were measured by an immune assay, Western blot, and qRT-PCR. SARS-CoV-2 infection induced severe oxidative stress, leading to enhanced extracellular release of HMGB1 and subsequent activation of signaling cascades to promote inflammation. Therefore, modulation of HMGB1’s proinflammatory signaling may reduce SARS-CoV-2-induced inflammation by controlling oxidative and inflammatory stress in COVID-19 disease. This study was supported by a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI) to YMH (grant I.D. number 123385), NIH/NIAID R21 AI35619 to YMH, and Rapid Response Pilot grant from NIEHS P30 Center Grant ES030285 to YMH. Additional support was from the Institute for Translational Science at UTMB, supported by a Clinical and Translational Science Award Mentored Career Development (KL2 Award; KL2TR001441), and Pilot grant (85393) from Institute for Human Infections & Immunity at UTMB, supported by Sealy & Smith Foundation to YMH.