Oxidative mechanisms are not only involved in chronic degenerative diseases but also in infectious diseases, among which viral respiratory diseases. Antioxidants have the capability to counteract the action of oxidants by scavenging reactive oxygen species (ROS) and by inhibiting oxidant generating enzymes. Overproduction of ROS and deprivation of antioxidant systems play a major role in COVID-19 occurrence, progression, and severity. Interconnected pathways account for the relationships between oxidative damage and inflammation resulting from an interplay between transcription factors having opposite effects. For instance, Nrf2 downregulates inflammation by inhibiting endogenous antioxidant enzymes such as NQO-1 and HO-1. On the other hand, NF-κB upregulates pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-8, PGE-2, COX-2, TNF-α, MMP-3, and MMP-4. A central protective role against oxidants is played by reduced glutathione (GSH), which is depleted in SARS-CoV-2 infection. N-acetylcysteine (NAC), a precursor of GSH, is of particular interest as an anti-COVID-19 agent. GSH and NAC hamper binding of the S1 subunit of SARS-CoV-2 spike proteins to the angiotensin-converting enzyme 2 (ACE2) receptor. In addition, NAC and its derivatives possess a broad array of antioxidant and antiinflammatory mechanisms that could be exploited for COVID-19 prevention and adjuvant therapy. In particular, as demonstrated in a previous clinical trial evaluating influenza and influenza-like illnesses, the oral administration of NAC may be expected to decrease the risk of developing COVID-19. Furthermore, at the very high doses used worldwide as an antidote against paracetamol intoxication, intravenous NAC is likely to attenuate the pulmonary and systemic symptoms of COVID-19.