This study was designed to evaluate the impact of methicillin resistance on the outcomes among patients withS. aureusosteomyelitis. We reviewed all extremity osteomyelitis patients treated in our clinic center between 2013 and 2020. All adult patients withS. aureuspathogen infection were included. Clinical outcome in terms of infection control, length of hospital stay, and complications were observed at the end of a 24‐month follow‐up and retrospectively analyzed between populations with/without methicillin resistance. In total, 482 osteomyelitis patients due toS. aureuswere enrolled. The proportion of methicillin-resistantS. aureus(MRSA) was 17% (82) and 83% (400) of patients had Methicillin-sensitiveS. aureus(MSSA). Of 482 patients, 13.7% (66) presented with infection persistence after initial debridement and antibiotic treatment (6 weeks), needed repeated debridement, 8.5% (41) had recurrence after all treatment end and a period infection cure, complications were observed in 17 (3.5%) patients (pathologic fracture; 4, nonunion; 5, amputation; 8) at final follow-up. Following multivariate analysis, we found patients withS. aureusosteomyelitis due to MRSA are more likely to develop a persistent infection (OR: 2.26; 95% CI 1.24–4.13) compared to patients with MSSA. Patients infected with MRSA also suffered more complications (8.5% vs. 2.5%, p = 0.015) and longer hospital stays (median: 32 vs. 23 days, p < 0.001). No statistically significant differences were found in recurrence. The data indicated Methicillin resistance had adverse clinical implication for infection persistence among patients withS. aureusosteomyelitis. These results will help for patients counsel and preparation for treatment.