The objective of this study was to evaluate the impact of ozone treatment on microbiological decontamination (intrinsic microflora and inoculated Listeria innocua) and some physicochemical characteristics and bioactive compounds of Cantaloupe melon juice, also during refrigerated storage. To determine adequate ozone exposure, the survival curve of L. innocua was previously assessed. A thermal treatment was also performed seeking comparison with ozone treatment impact. After ozone exposure, L. innocua was not detected in juice samples, while thermal pasteurization allowed a reduction of 5.2 ± 0.2 log cycles. Although ozone reduced the intrinsic microflora loads, this reduction was higher for heat‐treated samples. Vitamin C was highly retained in ozone‐treated juices (68%), when compared with the pasteurized ones (39%). After 13 days of storage, ozone allowed the retention of the most quality parameters analyzed and, therefore, it can be considered as a promising alternative to traditional pasteurization of Cantaloupe melon juice. Practical applications The actual consumers' demand for high‐quality food standards has launched research to alternative and milder nonthermal processes, which have gained increasing attention and importance in the fruit juice industries. Ideally, preservation and/or processing of foods should involve technologies that prevent undesirable microbial survival and minimize quality attributes changes and nutrient losses. Thermal treatments are conventionally used to attain such targets; however, the content and the biological activity of the most health‐related compounds are dramatically reduced. In this context, and particularly in the beverages industries, ozone has been exploited due to its potential for inactivating spoilage and pathogenic microorganisms, while being effective in overall quality retention of the products.