The COVID-19 pandemic presented humanity with numerous challenges, particularly in the fields of prevention and treatment. Oxygen-ozone therapy has been utilized in medicine for over a century, and its application in COVID-19 has been the subject of recent research and evaluation. This narrative literature review thesis analyzed 27 primary research papers, presenting the current state of the evidence on the mechanisms of action, effectiveness, and safety of ozone therapy in COVID-19 prophylaxis, treatment, and post-COVID-19 condition treatment as adjuvant and monotherapy. Three of the most common systemic routes of ozone therapy application in COVID-19 were evaluated: major-autohemotherapy (M-AHT), ozonized saline solution (O3SS), and rectal insufflation (RIO3). All studies reviewed demonstrated significant efficacy and high safety of ozone therapy, with minor transient adverse effects reported with the use of O3SS and RIO3. The main mechanism of action of ozone is through its derivatives, two main signaling molecules: reactive oxygen species (ROS) and lipid oxidation products (LOPs), which regulate numerous molecular pathways and result in the following therapeutic effects: antiviral, anti-inflammatory, antithrombotic, immune system modulation, modulation of oxidative stress, improvement of tissue oxygenation and circulation, and protection of the vascular endothelium. The thesis explains that the role of the nurse is in the safe preparation of the oxygen-ozone mixture, assistance in the administration of the prescribed therapy using different routes of application, education and preparation of the patients, and monitoring of the effects. Major autohemotherapy technique is explained together with a critical comparison of the use of three M-AHT sets commonly used in clinical practice.