Objectives. Previous studies have shown that hyperbaric oxygen (HBO) is effective in reducing the severity of acute distal colitis (ADC). Ozone therapy (OT) reduces inflammation in several pathological conditions. We aimed to compare the effects of HBO therapy and OT in an experimental ADC rat model. Materials and methods. Forty rats were randomly divided into four groups: Sham, ADC, ADC + HBO, and ADC + OT. Rats in the sham group were given isotonic saline. In the remaining groups, ADC was created by intracolonic administration of 4% acetic acid. No treatment was given to the ADC group. The rats in the ADC + HBO and ADC + OT groups were given HBO and ozone treatments, respectively. The administration of acetic acid caused an inflammatory response in all animals. Distal colons and blood samples were obtained. Results. The histopathological score was significantly higher in the ADC group compared to the other groups. The histopathological scores in the ADC + HBO and ADC + OT groups were significantly lower compared to the ADC group (both p < 0.001). The most pronounced therapeutic effect was observed in the ADC + OT group. Malondialdehyde and neopterin levels and superoxide dismutase and glutathione peroxidase activities in the ADC group were significantly higher compared to the other groups (p < 0.001). Conclusion. Our data showed that the therapeutic effect of OT is more pronounced than that of HBO therapy. Its possible effect is by means of decreasing inflammation, edema, and oxidative stress. These findings also suggest that it is possible to improve the outcome of ADC by using ozone therapy as an adjuvant therapy. © 2011 Informa Healthcare.