This study sought to assess clinical characteristics and differences in outcomes between children with Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-sensitive Staphylococcus aureus (MSSA) osteomyelitis or septic arthritis and whether initial antibiotic regimen affects patient outcomes. We analyzed records of children ages 15 days to 18 years admitted between 2009 and 2016 to two tertiary children’s hospitals who were diagnosed with an osteoarticular infection and had a microorganism identified. A total of 584 patients met inclusion criteria, of which 365 (62.5%) had a microbiological diagnosis. MSSA was the most common pathogen identified (45.5%), followed by MRSA (31.2%). Compared to MSSA, patients with MRSA had a higher initial C-reactive protein and longer hospitalization. Patients whose initial antibiotic regimens included vancomycin had a longer hospitalization than those initiated on clindamycin without vancomycin, even after removing sicker patients admitted to the pediatric intensive care unit. While MRSA was associated with increased severity of osteoarticular infections compared to MSSA, the incidence of MRSA has been declining at our institution. Patients with longer lengths of stay were more likely to be on vancomycin. Clindamycin should be considered in the initial antibiotic regimen for osteomyelitis and septic arthritis with ongoing surveillance of local microbiology and outcomes.