Leishmania major (Yakimoff & Schokhor, 1914), an important causative agent of Old World Cutaneous Leishmaniasis (CL), is transmitted by sand flies among a limited number of gerbilline reservoir-species. We can take advantage of this strong dependency to break the pathogen transmission cycle by using systemic insecticides that render the host toxic to the blood-feeding vector. We evaluated the potential of this approach with two novel reservoir species, incriminated for CL expansion in several sites in the Middle East. Specifically, we evaluated: 1) the residuality of the systemic insecticide fipronil in Meriones tristrami (Thomas, 1892) fed on fipronil-treated baits and 2) the treatments’ adulticide effect on sand flies that blood fed on treated and untreated M. tristrami and M. crassus (Sundevall, 1842). We fed M. tristrami with food pellets containing 0.1 g/kg fipronil and used gas chromatograph–mass spectrometery analysis and bioassays to examine its residual toxicity to blood-feeding female sand flies. In M. tristrami, fipronil was rapidly metabolized to fipronil sulfone, found in the blood, urine, and feces for ≥31 d after fipronil admission. The survival of sand flies that blood fed on fipronil-treated M. tristrami and M. crassus was significantly reduced for at least 15 and 9 d respectively, after fipronil admission. These results hold promise for the potential contribution of systemic control approaches to CL integrated management strategies against novel CL (due to L. major) outbreaks in Israel and elsewhere.