The emergence of antibiotic-resistant Staphylococcus aureus and its capacity for biofilm formation pose significant challenges in healthcare. Eugenol, a natural phenolic compound, has demonstrated potential as an antimicrobial agent, but its clinical application is hindered by issues like poor solubility and volatility. Advances in nanotechnology have addressed these limitations by functionalizing nanoparticles with eugenol, enhancing its stability, bioavailability, and antimicrobial efficacy. This systematic review critically examines the synergistic effects of eugenol-functionalized nanoparticles (EFNPs) against S. aureus, focusing on their potential to combat antibiotic resistance and disrupt biofilm formation. The analysis reveals that EFNPs significantly lower minimum inhibitory concentrations (MICs) and increase zones of inhibition compared to free eugenol. Additionally, EFNPs demonstrate strong antibiofilm activity, effectively preventing the formation of new biofilms and disrupting existing ones. Mechanistic insights suggest that EFNPs disrupt bacterial membranes, generate reactive oxygen species (ROS), and downregulate biofilm-associated genes, contributing to their antimicrobial and antibiofilm efficacy. With minimal cytotoxicity and no observed resistance development in S. aureus, EFNPs present a promising adjunct or alternative to conventional antibiotics. However, further research, including in vivo studies and clinical trials, is necessary to fully realize their potential in combating resistant bacterial infections.