Staphylococcus aureus (S. aureus) is a common pathogen that can cause many human diseases, such as skin infection, food poisoning, endocarditis, and sepsis. These diseases can be minor infections or life-threatening, requiring complex medical management resulting in substantial healthcare costs. Meanwhile, as the critically ignored “organ,” the intestinal microbiome greatly impacts physiological health, not only in gastrointestinal diseases but also in disorders beyond the gut. However, the correlation between S. aureus infection and intestinal microbial homeostasis is largely unknown. Here, we summarized the recent progress in understanding S. aureus infections and their interactions with the microbiome in the intestine. These summarizations will help us understand the mechanisms behind these infections and crosstalk and the challenges we are facing now, which could contribute to preventing S. aureus infections, effective treatment investigation, and vaccine development.