Background: Necrotizing soft tissue infections (NSTIs) require prompt surgical debridement and antimicrobial therapy. Indicated antimicrobial therapy involves broad-spectrum coverage against common pathogens and toxin inhibition. Linezolid provides both methicillin-resistant Staphylococcus aureus (MRSA) coverage and toxin inhibition, however, there is limited evidence evaluating its role in empiric treatment. The purpose of this study was to evaluate the impact of empiric linezolid use for NSTIs on the total duration of MRSA-active therapy. Patients and Methods: This retrospective, single-center study included adult surgical intensive care unit (ICU) patients treated with empiric vancomycin and clindamycin or linezolid along with gram-negative and anaerobe coverage for NSTIs. The primary end point of this study was the duration of MRSA-active therapy. Secondary end points included ICU and hospital length of stay (LOS; days), new-onset acute kidney injury (AKI), and Clostridioides difficile infection (CDI). Results: There were 21 patients in the vancomycin/clindamycin cohort and 28 patients in the linezolid cohort. The average duration of vancomycin was 3.9 days versus 2.9 days of linezolid (p = 0.04). The average hospital LOS for the vancomycin/clindamycin cohort was somewhat longer than the linezolid cohort, although the difference was not statistically significant (p = 0.07), and the incidence of new-onset AKI during hospitalization was higher in the vancomycin/clindamycin cohort (38.1% vs. 0%; p < 0.001). No differences were observed for ICU LOS or CDI. Conclusions: Empiric linezolid use for NSTI was associated with one less day of MRSA-active therapy and lower incidence of new-onset AKI during hospitalization. Linezolid was a safe and effective alternative to vancomycin/clindamycin for empiric treatment of NSTIs.