The organisms of the genus Leishmania are flagellated protozoan parasites and are the causative agents of leishmaniasis. This disease is a major health problem, especially in tropical countries. Currently, cutaneous leishmaniasis is treated by chemotherapy using pentavalent antimonials, but these drugs have serious organo-toxicity, drug resistance on several occasions, and low efficiency in controlling the infection. The present work is carried out to evaluate the in vitro antileishmanial activity of methanolic extracts and phytochemical fractions of two plants ethnobotanically used against leishmaniasis and skin infection, Calotropis procera and Rhazya stricta leaves against Leishmania major promastigote and amastigote stages and cytotoxicity against the Vero cell line. The leaves of C. procera and R. stricta were extracted with methanol and fractionated by petroleum ether, chloroform, ethyl acetate, n-butanol, and water. The methanolic extracts of the leaves of C. procera and R. stricta exhibited antileishmanial activity against L. major promastigotes with IC values of 66.8 and 42.4 µg mL, respectively. While their CC 2.3 and 298 µg mL and their SI 0.03 and 7.03 respectively. However, the fractionations of the methanolic extract of C. procera leaves revealed antiparasitic activity against both L. major promastigote and amastigote stages in vitro, which significantly increased with polarity with the exception of n-butanol. Hence the best activity was revealed by the water fraction (IC of 26.3 and 29.0 µg mL) for the two stages. In conclusion, further phytochemical investigation should be performed for the C. procera water extract in terms of antileishmanial active ingredient isolation that may enhance the possibility of avoiding toxic substances and overcome the low SI (1.1 and 1.01).