A novel series of benzothiazolyl-pyridine hybrids - and - were produced from the reaction of enamine derivative with each of the arylcyanoacetamides - and cyanoacetohydrazides -. The new products were characterized by spectral techniques (IR, H NMR, C NMR, and MS). Biological evaluation of - and - in against H5N1 and SARS-COV-2 viruses showed that several compounds had significant activity. Compounds -, which contain fluorine atoms, have better activity against H5N1 and anti-SARS-CoV-2 viruses than the other compounds included in this study. Compound has a trifluoromethyl group at position-3 of the phenyl ring and exhibits a high activity against H5N1 virus with 93 and 60% inhibition at concentrations of 0.5 and 0.25 μmol/μL, respectively, among the tested compounds, and it also showed anti-SARS-CoV-2 virus with a half-maximum inhibition rate of 3.669 μM, among the remaining compounds. The mechanism of action of -, which is expected to be repurposed against COVID-19, was investigated. The results showed that the compounds have virucidal effects at different stages of the three mechanisms of action. Furthermore, compounds - were found to possess CoV-3CL protease inhibitory activities with IC values of 544.6, 868.2, and 240.6 μg/mL, respectively, compared to IC = 129.8 μg/mL of the standard drug lopinavir. Interestingly, compounds - also showed high inhibitory activity against the H5N1 virus as well as the SARS-CoV-2 virus. Moreover, compounds - fit admirably into the active site of the SARS-CoV-2 main protease (PDB ID: 6LU7) using the molecular docking Moe software 2015.10.