SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation. SARS-CoV-2, a highly transmissible respiratory pathogen, causes severe multi-organ damage. This study reveals that SARS-CoV-2 increases mitochondrial transmembrane potential through the SARS-CoV-2 RNA-nucleocapsid cluster, leading to mitochondrial elongation and enhanced oxidative phosphorylation (OXPHOS), which boosts ATP production. SARS-CoV-2 also activates the EGFR-mediated cell survival signal cascade, promoting mitochondrial EGFR trafficking, which contributes to abnormal OXPHOS and viral propagation. Approved EGFR inhibitors, particularly vandetanib, significantly reduce SARS-CoV-2 propagation by inhibiting EGFR trafficking to mitochondria and restoring normal OXPHOS and ATP levels. Vandetanib treatment in SARS-CoV-2-infected hACE2 transgenic mice reduces viral load and lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants, including alpha, beta, delta, and omicron. These findings suggest that EGFR is a promising host target for combating SARS-CoV-2. SARS-CoV-2-induced mitochondrial alterations and EGFR trafficking during early infection play a critical role in viral propagation, highlighting the potential of EGFR inhibitors as therapeutic agents for COVID-19.SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation. SARS-CoV-2, a highly transmissible respiratory pathogen, causes severe multi-organ damage. This study reveals that SARS-CoV-2 increases mitochondrial transmembrane potential through the SARS-CoV-2 RNA-nucleocapsid cluster, leading to mitochondrial elongation and enhanced oxidative phosphorylation (OXPHOS), which boosts ATP production. SARS-CoV-2 also activates the EGFR-mediated cell survival signal cascade, promoting mitochondrial EGFR trafficking, which contributes to abnormal OXPHOS and viral propagation. Approved EGFR inhibitors, particularly vandetanib, significantly reduce SARS-CoV-2 propagation by inhibiting EGFR trafficking to mitochondria and restoring normal OXPHOS and ATP levels. Vandetanib treatment in SARS-CoV-2-infected hACE2 transgenic mice reduces viral load and lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants, including alpha, beta, delta, and omicron. These findings suggest that EGFR is a promising host target for combating SARS-CoV-2. SARS-CoV-2-induced mitochondrial alterations and EGFR trafficking during early infection play a critical role in viral propagation, highlighting the potential of EGFR inhibitors as therapeutic agents for COVID-19.