: 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 (IC50 = 43.08 and 34.28 µM, respectively). Among the eight 1,4‐DHPs that were active (IC50 < 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 (IC50 = 24.62 µM) and had a Selectivity Index (SI) higher than 4 compared to GM07492A cells. On the other hand, compound 9 (ethyl 2,7,7‐trimethyl‐4‐(2‐nitrophenyl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate) was the most active against L. amazonensis amastigotes (IC50 = 16.27 µM and SI = 6.1) after 24 h of treatment. Based on our results, asymmetric 1,4‐DHPs derived from dimedone exhibit antileishmanial potential.