Prior studies suggest Staphylococcus aureus exotoxins are not produced when the organism is cultured in human blood. Human blood was fractionated into plasma and water-lysed red blood cells, and it was demonstrated that mixtures of α and β globins of hemoglobin (as low as 1 μg/mL) inhibited S. aureus exotoxin production while increasing production of protein A and not affecting bacterial growth. Pepsin but not trypsin digestion destroyed the ability of α and β globin to inhibit exotoxin production. Exotoxin production by both methicillin-resistant and methicillin-susceptible organisms was inhibited. Production of streptococcal pyrogenic exotoxin A by Streptococcus pyogenes was unaffected by α and β globin chains but was inhibited when produced in S. aureus. Use of isogenic S. aureus strains suggested the targets of α and β globin chains, leading to inhibition of staphylococcal exotoxins, included the two-component system SrrA-SrrB. δ hemolysin production was also inhibited, suggesting the two-component (and quorum sensing) system AgrA-AgrC was targeted. The α and β globin chains represent promising molecules to interfere with the pathogenesis of serious staphylococcal diseases.