In the last decades, Staphylococcus aureus acquired a dramatic relevance in human and veterinary medicine for different reasons, one of them represented by the increasing prevalence of antibiotic resistant strains. However, antibiotic resistance is not the only weapon in the arsenal of S. aureus. Indeed, these bacteria have plenty of virulence factors, including a vast ability to evade host immune defenses. The innate immune system represents the first line of defense against invading pathogens. This system consists of three major effector mechanisms: antimicrobial peptides and enzymes, the complement system and phagocytes. In this review, we focused on S. aureus virulence factors involved in the immune evasion in the first phases of infection: TLR recognition avoidance, adhesins affecting immune response and resistance to host defenses peptides and polypeptides. Studies of innate immune defenses and their role against S. aureus are important in human and veterinary medicine given the problems related to S. aureus antimicrobial resistance. Moreover, due to the pathogen ability to manipulate the immune response, these data are needed to develop efficacious vaccines or molecules against S. aureus.