Widespread antibiotic usage has resulted in the rapid evolution of drug-resistant bacterial pathogens. Resolving how pathogens respond to antibiotics under different contexts is critical for understanding disease emergence. It remains unclear how interactions between hosts and antibiotics impact pathogen evolution. Here, we evolved Staphylococcus aureus, a major bacterial pathogen, varying exposure to host and antibiotics to tease apart the contributions of these selective pressures on pathogen adaptation. After 12 passages, S. aureus evolving in Caenorhabditis elegans nematodes exposed to a sub-minimum inhibitory antibiotic concentration became highly virulent, regardless of whether the ancestral pathogen was methicillin-resistant (MRSA) or methicillin-sensitive (MSSA). Host and antibiotic selected for reduced drug susceptibility in MSSA while increasing MRSA total growth outside hosts. We identified mutations in genes involved in regulatory networks linking virulence and metabolism,