Staphylococcus aureus causes diverse clinical manifestations, from asymptomatic colonization to severe invasive disease. Host genetic factors influencing infection susceptibility and severity remain incompletely understood. This systematic review, conducted according to PRISMA 2020 guidelines and registered in PROSPERO, evaluated human genetic variants associated with susceptibility to S.aureus infection and colonization, with subsequent clinical outcomes. Bibliographic databases and grey literature sources were searched for observational studies (2015-2026), with risk of bias assessed using the Newcastle-Ottawa Scale. Regarding innate immunity, IL1RN*2/*2 was associated with post-traumatic S. aureus osteomyelitis, whereas the TIRAP association lost significance after adjustment. In adaptive immunity, admixture mapping linked European ancestry at HLA class II locus to bacteremia in African Americans, while CCR5Δ32 altered circulating chemokines levels without altering clinical risk. Regarding metabolism and iron regulation, GLS2 variant (rs937115) was associated with complicated bacteremia, and an intergenic CHCHD7/SDR16C5 variant (rs73596248) was linked to higher hepcidin levels and a lower risk of bacteremia. CFTR F508del genotype showed no significant association with methicillin-resistant S. aureus (MRSA) acquisition. These findings support a multifactorial host genetic network in S. aureus infection and underscore the need for larger, multi-ancestry, independently replicated studies to validate genetic markers for future risk stratification.