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The interactome networks of innate immune molecules operating in the early process of Trypanosoma cruzi infection of human cells are unknown. Here we show that T. cruzi regulates the defensin alpha-1 interactome network and that human defensin alpha-1 plays a fundamental role in the initiation of cellular responses to T. cruzi. We demonstrate that human epithelial cells respond to early infection by up regulating the expression and secretion of defensin alpha-1, which causes trypanosome membrane pore formation and depolarization to inhibit T. cruzi motility, which prevents cellular infection. The pores formed in the flagellar membrane of the invasive trypanosomes cause the detachment of the flagellum from the trypanosome body to abolish trypanosome motility, which is required for trypanosome cell entry. This is the first report elucidating the defensin alpha-1 interactome network and showing that defensin alpha-1 disrupts the T. cruzi flagellum to compromise trypanosome motility and prevent cellular infection. Thus, defensin alpha-1 possesses remarkably distinct modes of activity against protozoan parasites than bacteria and viruses, and its actions may provide insights for the development of new anti-trypanosomal strategies. This work was supported by NIH grants AI080580 and AI007281.