Objective Ozone is a colorless gas used as a disinfectant and to treat diseases by limiting the effects of bacteria, viruses, fungi, yeast, and protozoa. In this study, we investigated the clinical efficacy of ozonated water lavage and physiological saline irrigation combined with vacuum-sealed drainage (VSD) in the treatment of chronic osteomyelitis. Methods Eighteen patients (14 men and 4 women) with chronic osteomyelitis in the limbs (tibia: 13 cases; femur: 4 cases; humerus: 1 case) admitted to our hospital between April 2012 and October 2018 were selected. The patients were aged 9 to 52 years, with a mean age of 31 years. All patients underwent ozonated water lavage and physiological saline irrigation combined with VSD negative pressure closed drainage during hospitalization. The patients were followed up for 18 to 84 months, with a mean of 31 months. Results Osteomyelitis recurred in only one case of nonunion. The length of hospitalization was 18 to 29 days, with a mean of 21 days. Conclusions A combination of ozonated water lavage, physiological saline irrigation, and VSD provided good clinical effects in the treatment of chronic osteomyelitis, and thus, is recommended for such treatment.