Staphylococcus aureus is a high-priority pathogen causing skin and soft tissue infections (SSTIs). The frequent resistance to anti-staphylococcal agents exhibited by this underscores the need for accurate diagnostics to guide effective therapy. Therefore, this study aimed to compare phenotypic and genotypic resistance in S. aureus isolates from nasal carriers and SSTIs and to elucidate gene-silencing mechanisms. In total, 355 S. aureus isolates (256 isolated from carriers and 79 from SSTIs) were studied for their phenotypic and genotypic resistance to β-lactams, macrolides, tetracyclines, aminoglycosides, and mupirocin. The silenced mupA gene (low prevalence: 0.6%; 2/335), linked to mupirocin resistance, was sequenced, and expression was assessed via reverse transcription qualitative PCR (RT-qPCR) in all mupA-positive isolates. SSTI isolates showed significantly higher resistance to erythromycin, gentamicin, and mupirocin, along with a higher prevalence of multidrug-resistant strains and ermC and tetM genes. Sequencing revealed multiple mutations in silent mupA, including a critical frameshift (c.372 delA) in a poly(A) tract that brings about premature truncation. RT-qPCR indicated upregulation of silent mupA variants and high variability in functional strains, suggesting that frameshift alone prevents resistance. These findings highlight silent resistance genes as key targets for advancing S. aureus surveillance and for combating emerging threats.