The sudden emergence of Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus Disease 2019 (COVID-19), burgeoned into a multi-year pandemic that continues to test the world’s healthcare systems and economies. Early therapeutic development led to multiple compounds that target early stages of the SARS-CoV-2 lifecycle with varying degrees of efficacy: monoclonal antibodies (e.g., Casirivimab, Tixagevimab) to block virus entry; protease inhibitors (e.g., Paxlovid) to block proteolytic cleavage of nonstructural proteins translated shortly after viral entry; and nucleoside analogues (e.g., Molnupiravir) to block viral RNA replication. However, later stages of the SARS-CoV-2 life cycle are relatively understudied and, consequently, late-stage inhibitors that could prove more effective or work synergistically with early-stage inhibitors are lacking. This dissertation work describes two host proteins that inhibit later SARS-CoV-2 lifecycle stages when modulated. PIKfyve inhibition was shown to block late lifecycle stages of SARS-CoV-2, in addition to broadly inhibiting early and middle stages, but exacerbated disease in a COVID-19 mouse model. Overexpression of the interferon stimulated gene 2’,3’-cyclic-nucleotide-phosphodiesterase (CNP) in vitro was shown to inhibit virion assembly by blocking SARS-CoV-2-induced mitochondrial depolarization and reactive oxygen species release. Additionally, overexpression of CNP in Balb/c laboratory mouse lungs reduced SARS-CoV-2 titers to undetectable levels at 2- and 4-dpi. Importantly, this work has identified host factors that could be further developed into therapeutic targets.