Staphylococcus aureus is a versatile pathogen known to cause hospital- and community-acquired, foodborne, and zoonotic infections. The clinical infections by S. aureus cause an increase in morbidity and mortality rates and treatment costs, aggravated by the emergence of drug-resistant strains. As a multi-faceted pathogen, it is imperative to consolidate the knowledge on its pathogenesis, including the mechanisms of virulence regulation, development of antimicrobial resistance, and biofilm formation, to make it amenable to different treatment strategies. Nanomaterials provide a suitable platform to address this challenge, with the potential to control intracellular parasitism and multidrug resistance where conventional therapies show limited efficacy. In a nutshell, the first part of this review focuses on the impact of S. aureus on human health and the role of virulence factors and biofilms during pathogenesis. The second part discusses the large diversity of nanoparticles and their applications in controlling S. aureus infections, including combination with antibiotics and phytochemicals and the incorporation of antimicrobial coatings for biomaterials. Finally, the limitations and prospects using nanomaterials are highlighted, aiming to foster the development of novel nanotechnology-driven therapies against multidrug-resistant S. aureus.