This study investigates the cellular alterations induced by SARS-CoV-2, focusing on its impact on mitochondrial bioenergetics and the EGFR signaling pathway. SARS-CoV-2 elevates mitochondrial transmembrane potential (ΔΨm) through the RNA-nucleocapsid cluster, leading to mitochondrial elongation and enhanced oxidative phosphorylation (OXPHOS) and ATP production. The virus also activates the EGFR signal cascade, promoting EGFR trafficking to mitochondria, which further supports abnormal OXPHOS and viral propagation. FDA-approved EGFR inhibitors, particularly vandetanib, significantly reduce SARS-CoV-2 propagation in vitro and in vivo, reducing lung inflammation and viral load in hACE2 transgenic mice. Vandanetinib exhibits potent antiviral activity against various SARS-CoV-2 variants, including alpha, beta, delta, and omicron. These findings suggest that EGFR is a promising therapeutic target for combating COVID-19.This study investigates the cellular alterations induced by SARS-CoV-2, focusing on its impact on mitochondrial bioenergetics and the EGFR signaling pathway. SARS-CoV-2 elevates mitochondrial transmembrane potential (ΔΨm) through the RNA-nucleocapsid cluster, leading to mitochondrial elongation and enhanced oxidative phosphorylation (OXPHOS) and ATP production. The virus also activates the EGFR signal cascade, promoting EGFR trafficking to mitochondria, which further supports abnormal OXPHOS and viral propagation. FDA-approved EGFR inhibitors, particularly vandetanib, significantly reduce SARS-CoV-2 propagation in vitro and in vivo, reducing lung inflammation and viral load in hACE2 transgenic mice. Vandanetinib exhibits potent antiviral activity against various SARS-CoV-2 variants, including alpha, beta, delta, and omicron. These findings suggest that EGFR is a promising therapeutic target for combating COVID-19.