Currently, there is no effective antiviral therapy recommended for the new coronavirus disease 2019 pneumonia (COVID-19). The purpose of this study was to evaluate the safety and efficacy of Ozonized Saline Solution (O3SS) used as a complementary therapy in adult patients with mild to severe COVID-19. Twenty-five adult patients who were hospitalized with mild to severe COVID-19 symptoms, who met the inclusion criteria and were being treated from April 3rd to April 26th, 2020, at the Viamed Virgen De La Paloma Hospital, Madrid, Spain were included in this study. Patients were allocated to receive standard care (SC) that included 200-400 mg hydroxychloroquine twice daily for 5-7 days plus Tocilizumab 400 mg twice daily for 5 days, low molecular weight heparin (LMWH) and 40 mg-60 mg metil-prednisone plus O3SS, 200 mL, 3-5 µg/mL daily for 10 days. Primary outcomes of treatment with O3SS were an improvement of clinical symptoms and a reduction in mortality. Secondary end points evaluated included participant clinical status, laboratory examinations, and duration of viral shedding. None of the patients treated with SC + O3SS died. Improvements in symptoms such as dyspnea, weakness, and reduction in body temperature were observed and corresponded with an improvement of laboratory finding including D-dimer, fibrinogen, LDH, and CRP. No side effects from the O3SS treatment were observed. Conclusions: COVID-19 patients with mild to severe symptoms who received intravenous O3SS as a complementary therapy demonstrated improved clinical symptoms, improved laboratory values and a reduction in mortality.