Abstract We have synthesized twenty‐three 1,4‐dihydropyridine derivatives (1,4‐DHPs) by using a microwave‐assisted one‐pot multicomponent Hantzsch reaction and evaluated their antibacterial activity against a representative panel of cariogenic bacteria and their in vitro antileishmanial activity against Leishmania ( L .) amazonensis promastigotes and amastigotes. Thirteen compounds were moderately active against Streptococcus sanguinis , Streptococcus mitis , and Lactobacillus paracasei . Compound 22 (diethyl 4‐(3‐methoxy‐4‐hydroxyphenyl)‐2,6‐dimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate) displayed moderate antibacterial activity against S. mitis and S. sanguinis , with a Minimum Inhibitory Concentration (MIC) of 500 μg/mL); compounds 8 (ethyl 2,7,7‐trimethyl‐4‐(3‐chlorophenyl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) and 10 (ethyl 2,7,7‐trimethyl‐4‐(3‐nitrophenyl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) were moderately active against S. sanguinis (MIC=500 μg/mL) and very active against L. amazonensis promastigotes (IC 50 =43.08 and 34.29 μM, respectively). Among the eight 1,4‐DHPs that were active (IC 50 <50 μM) against L. amazonensis promastigotes, compound 13 (ethyl 2,7,7‐trimethyl‐4‐(3,4,5‐trimethoxyphenyl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) was the most active (IC 50 =24.62 μM) and had a Selectivity Index (SI) higher than 4 compared to GM07492 A cells. On the other hand, compounds 7 (ethyl 2,7,7‐trimethyl‐4‐(3‐fluorophenyl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) and 9 (ethyl 2,7,7‐trimethyl‐4‐(2‐nitrophenyl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) were the most active against L. amazonensis amastigotes (IC 50 =12.53 and 13.67 μM, respectively; SI>7.9 and >7.3, respectively) after 24 h of treatment. Our results indicated that asymmetric 1,4‐DHPs derived from dimedone exhibit antileishmanial potential.