Potential toxicity, costs, and drug-resistant pathogens necessitate the development of new antileishmanial agents. Medicinal and aromatic plants constitute a major source of natural organic compounds. In this study, essential oils of Artemisia absinthium L. and Echinops keberichoMesfin were investigated by GC and GC/MS analyses. Isolated oils were screened for antileishmanial activity against two Leishmania strains (L. aethiopica and L. donovani), and toxicity on the human monocytic leukemia (THP-1) cell line and red blood cells in vitro. GC/MS Analysis revealed 65 compounds (93.74%) for Artemisia absinthium and 43 compounds (92.85%) for Echinops kebericho oil. The oils contained the oxygenated monoterpene camphor (27.40%) and the sesquiterpene lactone dehydrocostus lactone (41.83%) as major constituents, respectively. Both oils showed activity against promastigote (MIC 0.0097–0.1565 μl/ml) and axenic amastigote forms (EC50 0.24–42.00 nl/ml) of both leishmania species. Weak hemolytic effect was observed for both oils, showing a slightly decreased selectivity index (SI 0.8–19.2) against the THP-1 cell line. Among the two oils tested, E. kebericho exerted strong antileishmanial activity that was even higher than that of amphotericin B with significant cytotoxicity. This study, therefore, demonstrated the potential use of both oils as source of novel agents for the treatment of leishmaniasis.