Neglected tropical diseases (NTD) are a group of parasitic and bacterial diseases that affect thousands of people, mainly the population living in poverty, being neglected by pharmaceutical companies. Among these, Chagas disease affects approximately 6 million to 7 million people worldwide, with 75 million at risk of infection, which is considered a serious public health question. Despite alarming estimates, only the drugs nifurtimox and benznidazole are approved for the treatment, although they have severe side effects, justifying the efforts of medicinal chemistry to discover new analogs. Thus, this work aimed to perform a virtual screening using a covalent docking and MM-PBSA protocol in an FDA-approved drugs library dataset to search for new compounds useful against this disease. Initially, 1615 FDA-approved compounds were visually inspected for the presence of chemical groups reactive against cruzain reactive cysteine ​​(Cys²⁵), followed by the choice of the most suitable 3D structure for the virtual protocols. Thus, 241 compounds were selected and the covalent docking assays were performed using the GOLD^® software with the most appropriate 3D structure, and the compounds with a fit score covalent greater than 100, were selected to the MM-PBSA calculations, aiming to validate the screening results. Finally, the drugs neratinib, sacubitril, alprostadil, trandolapril, and florbetapir showed a covalent fit score between 102.14 and 116.59; ΔG_binding values ​​between -72.851 and -148,811 Kcal/mol calculated by MM-PBSA; and interactions with the key residues of the cruzain (Cys²⁵, His¹⁵⁹, Gly²³, and Gly⁶⁵), showing best values than other cruzain inhibitors experimentally assayed. Our findings suggest that these drugs may be possible cruzain inhibitors, and biological assays should be performed to confirm their potential.