AbstractIn this article, a series of 29 new pyrimidine N‐acylhydrazone hybrids were synthesized and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi protozoa that cause the neglected diseases cutaneous leishmaniasis and Chagas disease, respectively. Eight of the target compounds showed significant antiprotozoal activities with IC50 values in 4.3–33.6 μM range. The more active compound 4f exhibited selectivity index greater than 15 and drug‐like properties based on Lipinski's rule.