ABSTRACT The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial sought to evaluate the efficacy and safety of N-acetylcysteine as adjuvant therapy in hospitalized Iranian patients with COVID-19. Four different diets in 60 patients include; Kaletra (lopinavir/ritonavir) + hydroxychloroquine with/without N-acetylcysteine (600 mg TDS) and atazanavir/ritonavir + hydroxychloroquine with/without N-acetylcysteine (600 mg TDS), were administered in the study. At the end of the study, a further decrease in C-reactive protein was observed in groups with N-acetylcysteine (P =0.008), and no death occurred in the atazanavir/ritonavir + hydroxychloroquine + N-acetylcysteine group, showing that the combination of these drugs may reduce mortality. A significant rise in O2 saturation was observed in atazanavir/ritonavir+hydroxychloroquine+N-acetylcysteine group (P <0.05). Accordingly, oral or intravenous N-acetylcysteine, may enhance O2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and reduce mortality in hospitalized patients with COVID-19. The N-acetylcysteine could be more effective as prophylactic or adjuvant therapy in stable and non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation.