Staphylococcus aureus is known for its ability to acquire resistance to commonly used antibiotics and causes mastitis in cows. Bacterial strains belonging to this species can spread in humans and animals, through diffusion in different contexts, including workplaces and the environment. The antibiotic-resistance in S. aureus strains evidenced the need for novel therapeutic approaches that do not exert selective pressure on the evolutionary adaptation of the bacteria. Alternative approaches can be represented by anti-virulence therapies that interfere with virulence factors, or relative pathways that regulate the production of toxins. Various S. aureus toxins and regulatory systems involved in secreting these toxins can be investigated. The potential of targeting S. aureus toxins and virulence-mediated pathways as anti-virulence strategies can be a substantial and important alternative, in contrast to traditional antibiotics directed at pathogen viability but triggering the mechanisms of antibiotic-resistance. Thus, the antivirulence approach must be aimed to reduce the production of virulence factors without affecting bacterial growth. Strategies to reduce bacterial virulence include compounds able to inhibit quorum sensing, disassemble bacterial membranes, disrupt biofilm formation, or neutralize the bacterial toxin, thus reducing the spread of the infection. Virulence factors eventually related to the infectiousness of S. aureus strains can offer new insights into vaccine development and possible identification of new vaccine targets. The benefits of the antivirulence-antibiotic combination during the treatment against S. aureus infections have been enhanced by virtue of the synergistic action between antibiotics and the antivirulence compounds. The characteristics of the spread of antibiotic resistant S. aureus and its virulence characteristics for anti-virulence strategies have been described.