Epidemiological change in osteomyelitis had been observed for the past few years with a significant rise of chronic osteomyelitis by multidrug-resistant organisms (MDROs). It complicates antibiotic selection, and if not managed adequately, it results in amputation, sepsis, or death. This study was conducted for one year in a tertiary care hospital to identify the etiological agents and their response to antibiotics for the development of adequate management policy of osteomyelitis. Fifty seven patients were analysed, & the variables examined include epidemiological characteristics, risk factors, radiographic changes, histopathological features. Etiological agents were identified, and antimicrobial susceptibility testing was performed by an automated system. About 73.7% of the cases presented with chronic osteomyelitis in the age group of 31-40 years (29.3%). In 53 patients, it resulted from contagious microbial seeding. The most common site of infection was the metatarsal bones of the foot (38.6%). The common predisposing factor was Diabetes (36.8%). The most common causative organism was Staphylococcus aureus (46.9%). Methicillin resistance was 41.9%. Among Gram-negative isolates, Enterobacterales group predominated (22.7%), 42.9% of Gram-negatives were multidrug -resistant (MDR). In our study, we found an increased prevalence of chronic osteomyelitis of the extremities of the lower limb instead of acute hematogenous infection of the long bones. Most of them resulted from trauma or after fracture fixation device implantation or as a sequela of diabetic foot. Fourty percent of the etiological agents in our study were either methicillin resistant S. aureus (MRSA) or MDR Gram-negatives. This finding is challenging for the clinician to select the appropriate treatment option, reduce the risk of recurrence and improve the quality of life of the patients.