Staphylococcus aureus, a major gram positive bacterial pathogen that causes a wide spectrum of clinical infections, ranging from localized soft-tissue infections to life-threatening bacteremia and endocarditis. S. aureus infects tissues when the skin or mucosal barriers have been breached which leads to many different types of infections, including boils, carbuncles (a collection of boils) and abscesses. The present study envisaged the incidence of S. aureus in skin and soft tissue infection (SSTI), its susceptibility pattern to different antibiotics and molecular characterization isolated from three different hospitals of Odisha. Out of 1702 samples collected 1622(95.29%) were culture positive for different bacterial pathogens from which S. aureus was 356 (20.9%). The incidence rate of S. aureus among male and female group of patients was 57.5% and 42.2% respectively. The isolated S. aureus were resistant to most of the antibiotics such as azithromycin, penicillin, doxycycline, ciprofloxacin, tetracycline, gentamicin, ofloxacin, chloramphenicol, ampicillin and oxacillin. Further methicillin resistant S. aureus (MRSA)-95.8% were also identified from theS. aureus strains which were multi drug resistant and few were resistant to vancomycin (5%). The MRSA strains were confirmed genotypically by amplification of methicillin resistant (mecA- 63.3%) gene. Identification and antibiogram profile of S. aureus is highly essential for the treatment of sepsis patients in Odisha.