Indole-2-hydrazones 3–30 were synthesized and evaluated for their antileishmanial activity. The compounds 24 (IC50 = 1.86 ± 0.09 μM), 12 (IC50 = 2.26 ± 0.16 μM), 23 (IC50 = 3.81 ± 0.29 μM), 8 (IC50 = 4.01 ± 0.32 μM), 17 (IC50 = 4.89 ± 0.31 μM), 20 (IC50 = 4.89 ± 0.26 μM), 3 (IC50 = 5.12 ± 0.34 μM), 15 (IC50 = 5.26 ± 0.26 μM), 6 (IC50 = 6.16 ± 0.38 μM), and 21 (IC50 = 6.18 ± 0.045 μM) showed better activities than standard pentamidine (IC50 = 7.02 ± 0. 09 μM). Compounds 4, 5, 7, 9–11, 13, 16, 18, 19, 22, 25–28, and 30 displayed good activities. The compounds 14 and 29 were found to be inactive. The synthesized compounds were characterized by different spectroscopic techniques.