Background: Multiple drug-resistant tuberculosis (MDR-TB) is a growing public health threat. Oxidative stress is reckoned as one of the rate-limiting steps in the progression of TB. Oxidative stress increases the level of tissue injury and organ damage. The use of medical ozone therapy is gaining popularity due to its anti-microbial property and its homeostatic potential. Objectives: The present study investigates the role of ozone therapy in boosting the antioxidant status of MDR-TB patients. Methods: Medical Ozone therapy was given through rectal insufflations for 21 days in seven MDR-TB patients (five males and two females) who were under anti-Koch Treatment-4 were enrolled after obtaining written consent. The sessions were spaced out at a rate of three sessions per week. Blood serum and plasma samples were collected from the patients at the baseline and at the end of the 21st session to assess the antioxidant status of superoxide dismutase (SOD) and glutathione reductase (GR) and other biochemical parameters. Results: Statistically significant rise was observed in SOD (P = 0.028), but not in GR (P = 0.058). No other biochemical profiles showed any statistically significant change except for a reduction in serum glutamic-pyruvic transaminase (P = 0.026). Participants also expressed subjective improvement in their mental status. However, we have not used any validated scales to record their mental status. Conclusions:The present study suggests that ozone can be a promising medium in tackling the oxidative stress and enhancing the positive mental attitude in ailing MDR-TB patients. Therefore, it can be considered as adjuvant therapy in treating MDR-TB. However, there are major limitations like smaller sample size and lack of control group. Large scale randomized trials are warranted.