Recently, our in silico repositioning-chemogenomics approach predicted paroxetine (PAR), an antidepressant drug, as a inhibitor of Schistosoma mansoni serotonin transporters (SmSERTs), and consequently, a new anti-schistosomal candidate. With the aim of determining the anti-schistosomal activity of this drug, we initially used a spectrophotometric assay to determine activity against schistosomula worms. During this investigation, we verified that PAR showed a pronounced effect on schistosomula viability (IC50 = 2.5 μM) after 72 h of incubation. Then, we performed ex vivo studies with adult S. mansoni worms using a new automated image-based assay to accurately measure worm motility. As expected from the PAR's predicted mechanism of action, both male and female worms treated with low concentrations of PAR exhibited enhanced motility followed by reduction in motility as incubation time increased. PAR EC50 values for motility reduction in male and female worms were 5.1 μM and 9.9 μM after 24 h of exposure, respectively, and this effect was maintained until the end of the experiment (72 h). Lastly, homology modeling and docking studies with SmSERT-A and human SERT (hSERT) revealed insights into the chemical basis of PAR antischistosomal activity. These results provide crucial guidance for further studies to optimize PAR in terms of potency and selectivity.