COVID-19 is a newly discovered deadly disease with no proven definitive treatment until now. It is now proved that it can affect different body organs which necessitate intensive care management. Ozone (O3) therapy was used before for treating various viral infections like hepatitis B, human immune deficiency virus (HIV), and Ebola viruses. O3 also can manage hypoxia and increase tissue oxygenation, besides its anti-inflammatory and immunomodulatory properties which may have an important role in the management of cytokine storm. We used rectal O3 insufflation therapy assuming that it may have a beneficial role in the management of COVID-19 disease. Two sessions of rectal O3 therapy were given to a 60-year-old female patient who was confirmed COVID-19 positive. Before applying O3 therapy, she was hypoxic (sPO2:90%) despite mechanical ventilation with high fraction inspired oxygen (FiO2:90%). After therapy, she was markedly improved and discharged to the inpatient ward and then discharged home on day 10 post-admission. Another 40-year-old male patient who was confirmed COVID-19 positive and was home isolated received one session of O3 therapy. Before therapy, he was hypoxic (sPO2:85% on room air and 95% with O2 face mask 5 L/min). The patient showed gradual improvement over the next 3 days after therapy and becomes oxygen-independent (sPO2 became 94-97% on room air). No adverse effects were noticed in both cases. Rectal O3 insufflation can be used safely as adjuvant management for patients with COVID-19 disease.