The SARS-CoV-2 pandemic has resulted in millions of infections and deaths worldwide. Severe COVID-19 is associated with a dysregulated hyperinflammatory immune response, in part, characterized by the release of pro-inflammatory cytokines through inflammasome mediated pathways. This has led to a huge interest in targeting inflammatory mediators and their key activation pathways as COVID-19 therapeutics. Programmed Cell Death is known to drive inflammatory processes via caspase-mediated activation cascades, however the molecular mechanisms underlying these events during SARS-CoV-2 infection remain poorly understood. To address this, we developed and characterized a mouse adapted strain of SARS-CoV-2, derived from a clinical isolate. Multiple passaging of the virus in C5BL6/7 mice resulted in a more virulent strain (JCP21) that causes weight loss, inflammation and lung pathology in young mice and is deadly in old animals, thus reflecting key aspects of human COVID-19 disease. We used a gene-targeted approach to understand the role of cell death and inflammation in SARS-CoV-2 pathogenesis and disease. Infection of mice lacking the pro-inflammatory cytokine IL-1β displayed mitigated disease and decreased viral burden. However, loss of lytic cell death by deletion of pyroptosis initiators Caspase1/11/12 or effectors Gasdermin D, E, C or A or the necroptosis initiator RIPK3 or effector MLKL alone had no effect on disease or viral burden. Interestingly, the loss of Caspase-8-driven apoptosis rescued weight loss, but had no impact on viral load. Combined deficiency of pyroptosis, necroptosis and apoptosis pathways (Caspase1/11/12/8/Ripk3-/-) caused significant amelioration of both disease and viral burdens in mice, demonstrating the functional redundancy of the main cell death pathways during SARS-CoV-2 infection. Together, our data suggests that Caspase-1 and Caspase-8 can both drive disease during SARS-CoV-2 infection via the release of pro-inflammatory cytokines through the NLRP3 inflammasome pathway. We are currently exploring pharmacological approaches targeting these key caspases as therapeutic to ameliorate disease in wild type mice.