Most recently, severe acute respiratory syndrome coronavirus-2 has triggered a global pandemic without successful therapeutics. The goal of the present study was to define the antiviral effect and therapeutic action of blue light irradiation in SARS-CoV-2-infected cells. Vero cells were infected with SARS-CoV-2 (NCCP43326) or mock inoculum at 50 pfu/well. After blue light irradiation, the inhibitory effect was assessed by qPCR and plaque reduction assay. When Vero cells were irradiated to blue light ranging from 1.6 to 10 J cm Ă2 , SARS-CoV-2 replication was inhibited by up to 80%. The antiviral effect of blue light irradiation was associated with translation suppression via the phosphorylation of eIF2a by prolonging endoplasmic reticulum (ER) stress. The levels of LC3A/B and Beclin-1, which are key markers of autophagy, and the levels of PERK and PDI for ER stress were highly increased, whereas caspase-3 cleavage was inhibited after blue light irradiation in the later stage of infection. Our data revealed that blue light irradiation exerted antiviral and photo-biogoverning activities by prolonging ER stress and stimulating autophagy progression during viral infection. The findings increase our understanding of how photo-energy acts on viral progression and have implications for use in therapeutic strategies against COVID-19.Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; 2-DE/MALDI-TOF, 2-dimensional gel electrophoresis/matrix-assisted laser desorption/ionizationtime of flight; ER, endoplasmic reticulum; LC3, light chain 3; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PDI, protein disulfide isomerase; LASP-1, LIM and SH3 domain protein 1; TCTP, translationally controlled tumor protein; ENO-1, alpha-enolase; NAC, N-acetylcysteine; eIF2a, eukaryotic translation initiation factor 2 alpha.