Repurposing of known drugs and compounds as anticoronavirus disease 2019 (anti-COVID-19) agents through biological reevaluation of their activities, especially the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activities, is a new viable trend in drug discovery for the COVID-19 pandemic in 2020. Comprehensive inhibition of the enzymes and proteins of coronavirus and coronavirus 2 (i.e., multitarget inhibition) can be considered one of the most promising strategies for the development of highly potent remedies for COVID-19. However, almost all the reported inhibitors of the different life cycle stages of SARS-CoV-2 lack extreme potency against the major and fateful SARS-CoV-2 enzymes (e.g., RNA-dependent RNA polymerase “RdRp”, papain-like protease “PLpro”, and main protease “Mpro”). Herein, two antioxidant polyphenolic 1,3,4-oxadiazole compounds previously synthesized by me were repurposed and introduced, 1,2,3-tris[5-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazol-2-yl]propan-2-ol (named CoViTris2020) and 5-[5-(7-chloro-4-hydroxyquinolin-3-yl)-1,3,4-oxadiazol-2-yl]benzene-1,2,3-triol (named ChloViD2020), as the first multitarget SARS-CoV-2 inhibitors with higher potencies than other drugs reported to date (about 65, 171, and 303.5 times for CoViTris2020 and 20, 52.5, and 93 times for ChloViD2020 compared to those of remdesivir, ivermectin, and favipiravir, respectively). These two unique 2,5-disubstituted-1,3,4-oxadiazole derivatives were computationally studied (through molecular docking in almost all SARS-CoV-2 proteins and one human protein) and biologically evaluated (through one of the most credible in vitro anti-COVID-19 assays) for their anti-COVID-19 activities. The results of the computational docking showed that CoViTris2020 and ChloViD2020 exhibited very high inhibitory binding affinities with most of the docked SARS-CoV-2/human proteins (e.g., they exhibited low binding energies of −12.00 and −9.60 kcal mol⁻¹, respectively, with RdRp-RNA). Interestingly, the results of the biological assay showed that CoViTris2020 and ChloViD2020 exhibited very high and extremely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC₅₀ = 0.31 and 1.01 μM, respectively). Additionally, they may also be very promising lead compounds for the design and synthesis of new anti-COVID-19 agents (through structural modifications and further computational studies). Therefore, further investigations for the development of CoViTris2020 and ChloViD2020 as anti-COVID-19 drugs through in vivo biological evaluations and clinical trials are necessary. In brief, the development of CoViTris2020 and ChloViD2020 as the first two members of the new and promising class of anti-COVID-19 polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives will result in a therapeutic revolution for the treatment of SARS-CoV-2 infection and its accompanying COVID-19.