Staphylococcus aureus is an opportunistic pathogen that utilizes a diverse arsenal of complement evasin (CE) proteins to subvert the host immune response. This study has two main objectives: 1) To identify the core virulence regulatory mechanisms that control CE expression; 2) To determine how CE expression changes under different physiologically relevant conditions. We utilized novel GFP-reporter strains to monitor CE promoter activity under various physiologically relevant conditions, including pyruvate exposure, iron restriction, oxidative stress, and serum exposure. Significant differential CE gene expression was observed in response to specific environmental cues. Focusing on serum exposure, we identified three key two-component systems - SaeRS, GraRS, and ArlRS - that promote CE expression during short-term (2-hour) exposure to low serum levels. Our findings demonstrate that these major regulatory systems play distinct and sometimes opposing roles in the control of complement evasion. Importantly, CE regulation is not uniform; our data suggest that CEs should be reclassified based on their global regulatory divergence. We further discovered that specific antimicrobial peptides drive serum-mediated enhancement of CE expression, primarily through the SaeRS two-component system. These results provide new insight into how S. aureus rewires its virulence networks in response to serum, ultimately enhancing the expression of complement-targeting virulence factors. The rise of methicillin-resistant S. aureus (MRSA) strains, alongside worsening antimicrobial resistance, underscores a need to further dissect S. aureus pathogenesis. Deepening understanding of complement evasion regulation may offer effective novel targets for future MRSA vaccine research.