The inflammation of bone and bone marrow due to an infectious etiology is called osteomyelitis. Although almost all microorganisms, including bacteria, viruses, fungi, and so on, can cause osteomyelitis, the most common organism responsible for osteomyelitis is Staphylococcus aureus. When there is persistence of infection in the bone and bone marrow, it is termed chronic osteomyelitis. When patients suffering from osteomyelitis do not respond to appropriate therapeutic interventions for at least 4–6 weeks, they are referred to as having refractory osteomyelitis. It commonly happens after a grossly contaminated complicated fracture, but it can also happen after prosthetic joint replacement and fracture internal fixation surgery. It compromises the mobility, functional status, and independence, especially when it affects the young population in the productive age group. The pathophysiology of osteomyelitis starts when an infection affects the bone either from the hematogenous, or contiguous spread, or by the direct inoculation of infection from trauma or surgery. The clinical presentation of refractory osteomyelitis is varied, and there are no specific symptoms or signs to diagnose a case of refractory osteomyelitis. The clinical features may be persistent or even occur recurrently after a period of quiescence. The Cierny-Mader Classification is the widely used classification system for osteomyelitis, which takes into consideration of the physiologic class of the patient, the extent of bone involvement, as well as the systemic factors. The diagnosis of refractory osteomyelitis needs careful history taking along with laboratory and radiological investigations. It is a difficult-to-treat condition and is associated with significant morbidity, mortality. It is management requires treatment with antibiotics for a long duration, staged surgeries, prolonged hospital stay, and high cost of therapy. A multidisciplinary team effort is required for its better management. Hyperbaric oxygen (HBO2) therapy could be considered as an adjuvant therapy in the management of refractory osteomyelitis. To get the best results, HBO2 is to be administered along with culture-directed antibiotics and adequate surgical debridement.