The ultimate objective of this review is to encourage a multi-disciplinary and integrated methodological approach that, starting from the recognition of some current uncertainties, helps to deepen the molecular bases of ozone treatment effects on human and animal well-being and to optimize their performance in terms of reproducibility of results, quality, and safety. In fact, the common therapeutic treatments are normally documented by healthcare professionals’ prescriptions. The same applies to medicinal gases (whose uses are based on their pharmacological effects) that are intended for patients for treatment, diagnostic, or preventive purposes and that have been produced and inspected in accordance with good manufacturing practices and pharmacopoeia monographs. On the contrary, it is the responsibility of healthcare professionals, who thoughtfully choose to use ozone as a medicinal product, to achieve the following objectives: (i) to understand the molecular basis of the mechanism of action; (ii) to adjust the treatment according to the clinical responses obtained in accordance with the principles of precision medicine and personalized therapy; (iii) to ensure all quality standards.