The mechanism by which perifosine induced cell death in Leishmania donovani and L. amazonensis is described in this study. The drug reduced Leishmania mitochondrial membrane potential, decreased cellular ATP levels while increasing phosphatidylserine externalization. Perifosine did not increase membrane permeabilization. We also found that the drug inhibited the phosphorylation of Akt in the parasites. These results highlight the potential use of perifosine, as an alternative to miltefosine, against Leishmania.