Buffalo fly (Haematobia irritans exigua) infestation in cattle poses a significant challenge to animal health and welfare, causing blood loss and often painful skin lesions. These lesions can reduce the value of cattle in saleyards, make cattle unacceptable for certain markets, and provide a focus for secondary infections; yet, the underlying mechanisms of susceptibility remain poorly understood. This study employed SWATH-MS-based quantitative proteomics to investigate systemic proteomic profiles in lesion-susceptible (HL) and lesion-resistant (NL) cattle across multiple time points, aiming to identify key proteins and pathways associated with lesion development and resilience.