Staphylococcus aureus employs an array of virulence factors to aid in its pathogenesis. A subset of cytotoxins termed bi-component leucocidins have been characterized as important determinants in the host-pathogen interaction in S. aureus infections. While they have been studied over a century, bi-component leucocidins’ complex mechanisms in pathogenesis have not been fully elucidated. Secreted as monomers, with the exception of LukAB/GH, many combinations of the S- (HlgA, HlgC, LukE, LukS, LukA/H) and F- (HlgB, LukD, LukF, LukB/G) components have demonstrated cell lysis via pore formation and a magnified proinflammatory response at sublytic concentrations. While studies have described various host cellular receptors and therapeutic strategies to evade leucocidin binding, a common receptor for all the leucocidins has yet to be classified. Challenges in data extrapolation have occurred due to non-native protein expression methods and species specificity of the leucocidin components. In turn, developing successful therapeutic strategies has proven problematic with a need for multimodal therapy. Thus, our studies aimed to clarify the bi-component leucocidins’ cytotoxic effects on multiple subsets of leukocytes using a native protein expression system and to identify a novel human leukocyte receptor common to all leucocidins. Overall, combinations with HlgA and LukE demonstrated the highest degrees of cytotoxicity against PMNs and PBMCs. Coronin 1A was discovered as a common receptor for all cognate pairs of bi-component leucocidins, except LukAB/GH. In conclusion, our results have expanded the knowledge of the cellular targets for leucocidin cytotoxicity and have described a common leucocidin receptor as a potential therapeutic target against the bi-component leucocidins.