Electrochemical analyses aided by density functional theory calculations were used to investigate the oxidative degradation of pyrazine antiviral drugs, 3-hydroxypyrazine-2-carboxamide (T-1105) and 6-fluoro-3-hydroxypyrazine-2-carboxamide (favipiravir, T-705), by the electrogenerated superoxide radical anion (O₂^•–). T-1105 and T-705 are antiviral RNA nucleobase analogues that selectively inhibit the RNA-dependent RNA polymerase. They are expected as a drug candidate against various viral infections, including COVID-19. The pyrazine moiety was decomposed by O₂^•– through proton-coupled electron transfer (PCET). Our results show that its active form, pyrazine-ribofuranosyl-5′-triphosphate, is easily oxidized under inflamed organs by overproduced O₂^•– through the PCET mechanism in the immune system. This mechanistic study implies that the oxidative degradation of pyrazine derivatives will be prevented by controlling the PCET through simple modification of the pyrazine structure.