Background: Staphylococcus aureus is considered a normal flora by colonization in the nose and skin of humans, yet it is a major cause of nosocomial infections and a life-threatening pathogen. Among antibiotics, oxazolidinones and glycopeptides have activity against gram-positive pathogens. Objectives: The present study aimed to determine the frequency and comparison of the minimum inhibitory concentration of tedizolid, linezolid, and vancomycin against extensively drug-resistant (XDR) S. aureus strains isolated from hospitalized patients. Methods: This descriptive-analytical study was performed on 58 S. aureus isolates collected from 164 hospitalized patients over the course of one year. The Kerby-Bauer test was used to identify XDR isolates. Broth microdilution test was used according to CLSI M100-S25 (2015) criteria to determine the minimum inhibitory concentration (MIC) of vancomycin, linezolid, and tedizolid. Results: The frequency of XDR S. aureus clinical isolates was 28 (48.3%). Determining MIC showed that all XDR S. aureus isolates tested were susceptible to tedizolid (MIC, ≤ 2 μg/mL), while 92/8% (MIC, ≤ 4 μg/mL) and 60.70% (MIC, ≤ 2 μg/mL) of XDR isolates were categorized as susceptible to linezolid and vancomycin, respectively. The concentration of tedizolid that inhibited 90% of isolates (MIC90) was 2 μg/mL, 2-fold lower than linezolid (MIC90 = 4 μg/mL) and 64-fold lower than vancomycin (MIC90 = 128 μg/mL). There was a significant difference between the frequency of XDR isolates from the aspirate, trachea, and wound infections, so 22% of vancomycin-resistant isolates and all strains resistant to linezolid were isolated from hospitalized patients in the infectious ward (P = 0.04). Conclusions: We conclude that tedizolid has a beneficial effect on XDR isolates of S. aureus and possesses more potent in vitro activity than the rest agents.