Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory pathogen leading to serious multi-organ damage. However, little is known about SARS-CoV-2-induced cellular alterations for understanding robust virus propagation yet. Here we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates epidermal growth factor receptor (EGFR)-mediated cell survival signal cascade for sustaining persistence of SARS-CoV-2. We found that SARS-CoV-2 causes increase in mitochondrial transmembrane potential by SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) process followed by abundant ATP production. SARS-CoV-2 also activated EGFR signal cascade and subsequent mitochondrial EGFR accumulation which contributes to the maintenance of abnormal OXPHOS and viral propagation. Therapeutic options for the treatment of COVID-19 are still inadequate. The FDA-approved EGFR inhibitors caused a remarkable reduction in SARS-CoV-2 propagation. Among EGFR inhibitors, vandetanib showing the highest anti-SARS-CoV-2 efficacy exhibited the potent antiviral activity against various SARS-CoV-2 variants including B.1.1.7 (UK variant) and B.1.351 (SA variant) lineages in both in vitro cell culture and in vivo animal experiments using wild-type aged mouse susceptible to SARS-CoV-2 infection, suggesting that EGFR is an attractive host target for combatting COVID-19. Overall, our results suggest that SARS-CoV-2 induces aberrant mitochondrial dynamics and bioenergetics, which significantly contributes to robust SARS-CoV-2 propagation.