<p><italic>Staphylococcus aureus</italic> is one of the leading agents of nosocomial and community-acquired infections. In this study, we explored the genomic characterization of eight methicillin-resistant clinical isolates of <italic>S. aureus</italic> from Dhaka, Bangladesh. Notably, all strains were resistant to penicillin, cephalosporins, and monobactams, with partial susceptibility to meropenem and complete susceptibility to amikacin, vancomycin, and tigecycline antibiotics. The strains were found to have an average genome size of 2.73 Mbp and an average of 32.64% GC content. Multi-locus sequence typing analysis characterized the most predominant sequence type as ST361, which belongs to the clonal complex CC361. All isolates harbored the <italic>mecA</italic> gene, often linked to SCC<italic>mec</italic>_type IV variants. Multidrug resistance was attributed to efflux pumps NorA, NorC, SdrM, and LmrS alongside genes encoding beta-lactamase BlaZ and factors like ErmC and MepA. Additionally, virulence factors including <italic>adsA</italic>, <italic>sdrC</italic>, <italic>cap8D</italic>, <italic>harA</italic>, <italic>esaA</italic>, essC, <italic>isdB</italic>, <italic>geh</italic>, and <italic>lip</italic> were commonly identified. Furthermore, genes associated with heme uptake and clumping were present, highlighting their roles in <italic>S. aureus</italic> colonization and pathogenesis. Nine secondary metabolite biosynthetic gene clusters were found, of which six were common in all the strains. Numerous toxin-antitoxin systems were predicted, with ParE and ParB-like nuclease domains found to be the most prevalent toxin and antitoxin, respectively. Pan-genome analysis revealed 2007 core genes and 229 unique genes in the studied strains. Finally, the phylogenomic analysis showed that most Bangladeshi strains were grouped into two unique clades. This study provides a genomic and comparative insight into the multidrug resistance and pathogenicity of <italic>S. aureus</italic> strains, which will play a crucial role in the future antibiotic stewardship of Bangladesh.</p>