This cross-sectional study investigated the Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) nasopharyngeal carriage epidemiology in Accra approximately five years post-pneumococcal conjugate vaccines introduction in the country. Archived nasopharyngeal swabs collected from 410 children aged under five years old were bacteriologically cultured. The resultant S. aureus isolates were subjected to antimicrobial susceptibility testing and screening for carriage of the mecA and LukF-PV (pvl) genes, following standard procedures. The data obtained were analyzed with Statistical Products and Services Solutions (SPSS) using descriptive statistics and Chi square tests of associations. The isolated bacteria decreased across coagulase-negative Staphylococci (47.3%, n = 194), S. aureus (23.2%, n = 95), Diphtheroids (5.4%, n = 22), Micrococcus species (3.7%, n = 15), Klebsiella pneumoniae (3.2%, n = 13), Moraxella species and Citrobacter species (1.5% each, n = 6), Escherichia coli, Enterobacter species, and Pseudomonas species (0.9% each, n = 2). The MRSA carriage prevalence was 0.49% (n = 2). Individuals aged 37–48 months recorded the highest proportion of S. aureus carriage (32.6%, 31/95). Resistance of S. aureus to the antibiotics tested were penicillin G (97.9%, n = 93), amoxiclav (20%, n = 19), tetracycline (18.9%, n = 18), erythromycin (5.3%, n = 5), ciprofloxacin (2.1%, n = 2), gentamicin (1.1%, n = 1), cotrimoxazole, clindamycin, linezolid, and teicoplanin (0% each). No inducible clindamycin resistance was observed for the erythromycin-resistant isolates. Three (3.2%) of the isolates were multidrug resistant, of which 66.7% (2/3) were MRSA. The pvl gene was associated with 59.14% (55/93) of the methicillin-sensitive S. aureus (MSSA) isolates, but was not detected among any of the MRSA isolates.