Leishmaniases are a group of diseases caused by the protozoan parasites of the genus Leishmania. Despite the tremendous progress made in the understanding of the biochemistry and molecular biology of the parasite, the first choice treatment for leishmaniases still relies on pentavalent antimonial developed more than 50 years ago. These drugs are potentially toxic and often ineffective. The spread of drug resistance, combined with other shortcoming of the available antileishmanial drugs, emphasizes the importance of developing new effective, and safe drugs against leishmaniasis. The study reported here was undertaken to examine the antileishmanial activity of novel substituted 1,2,3,4-tetrahydropyrimidine-5-carboxamide (I) or cabohydrazide (II) analogs both in vivo and in vitro against Leishmania major. All tested compounds showed in vitro antileishmanial activity, but only four compounds showed in vivo activity in Swiss strain albino mice model as revealed by clinical cure of the cutaneous lesion, parasitologically by marked reduction in parasitic load and by histopathological changes.