Two types of regioisomeric chromene-based chalcones namely, 1-(6-methoxy-2H-chromen-3-yl)-3-phenylpropen-1-ones and 3-(6-methoxy-2H-chromen-3-yl)-1-phenylpropen-1-ones were prepared and investigated for their antileishmanial activity against promastigotes form of Leishmania major. The obtained results from in vitro biological assays indicated that chloro-substituted 1-(6-methoxy-2H-chromen-3-yl)-3-phenylpropen-1-ones exhibited excellent activity against Leishmania major at non-cytotoxic concentrations.