Previously, the treatment of Staphylococcus aureus infections was less complex, as most of those isolated were susceptible to β-lactam antibiotics. In recent years, there has been a marked increase in the incidence of invasive community-acquired (CA) methicillin-resistant S. aureus (MRSA) among children worldwide. However, data on the clinical characteristics and outcomes related to pediatric bone and joint infections caused by CA-S. aureus are very limited in India. In this tertiary hospital-based study, 74 patients with invasive S. aureus less than 18 years of age were identified between January 2004 and December 2008. All patients fulfilled the case definition of CA-S. aureus with evidence of infection before admission; they presented to our hospital without previous antibiotic use and were culture positive for S. aureus within 48 h of admission. All data including demographics, clinical features, treatment protocol, laboratory findings, and antimicrobial susceptibilities were recorded and compared using the SPSS 11.5 statistical software. Of the 74 patients with culture-positive S. aureus bone and joint infection, 41 had MRSA (55%). Forty-nine patients (66.2%) had osteomyelitis, of whom 29 (59.18%) had MRSA and 25 (33.7%) had septic arthritis, of whom 12 (48%) had MRSA. The MRSA group had a significantly higher erythrocyte sedimentation rate, C-reactive protein value, neutrophil count, and white blood cell count (P<0.05). The MRSA group also had longer duration of febrile days, hospital stay, and antibiotic course compared with the methicillin-susceptible S. aureus (MSSA) group (P<0.05). A clinical predictive algorithm was developed using seven significant independent multivariate predictors, with the probability of MRSA being 94% if all seven predictors were positive and 9% if five predictors were positive. Resistance to many classes of antibiotics was noted among S. aureus isolates including trimethoprim–sulfamethoxazole (MRSA 80%, MSSA 24%), erythromycin (MRSA 83%, MSSA 67%), clindamycin (MRSA 54%, MSSA 34%), and ciprofloxacin (MRSA 61%, MSSA 48%). No vancomycin resistance was observed. The morbidity associated with MRSA bone and joint infection in children is significantly higher than that caused by MSSA. Early diagnosis at the primary healthcare level and treatment with appropriate antistaphylococcal therapy are crucial to achieve optimal clinical outcomes. High levels of antimicrobial resistance of both MSSA and MRSA isolates to several classes of antibiotics are a major concern warranting the need for antimicrobial stewardship and ongoing surveillance.