Background/Objectives: Recent reports have demonstrated the antiparasitic activity of 1,4-dihydropyridine (1,4-DHPs). This study aimed to assess the in vitro antischistosomal activity of 24 1,4-DHPs against Schistosoma mansoni adult worms. Methods: Sixteen hexahydroquinolines (1–16) and eight Hantzsch esters (17–24) previously obtained through a multicomponent Hantzsch reaction were tested in vitro against Schistosoma mansoni adult worms. In silico studies with the most active compounds were also carried out. Results: Among the tested compounds, the Hantzsch esters 20 (diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) and 21 (diethyl 4-(3-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) provided the lowest IC50 (15.2 and 13.1 µM, respectively) and the highest selectivity for this parasite (SI = 2.31 and >4.59, respectively). Conclusions: Docking studies revealed that compound 21 has a high affinity for the S. mansoni target (PDB ID: 6UY4). Furthermore, ADMET predictions indicated that compound 21 meets the drug-likeness criteria without violating any Lipinski, Veber, or Egan’s rules.