A chemical library comprising substituted 3-nitroisoxazoles and 3-aminoisoxazoles was prepared and screened for their antileishmanial activity against L. donovani. As compared to Miltefosine, the standard drug used in bioassays, several compounds displayed remarkably better inhibition of the promastigote and amastigote stages of parasites. The in vivo evaluation of a few compounds in a golden hamster model showed significant reduction of the parasite load post treatment via the intraperitoneal route by several compounds. The preliminary pharmacokinetic evaluation of a representative compound 4mfvia the oral route, however, indicated high systemic clearance from the body.