Due to widespread multi-drug resistance in parasitic nematodes of livestock animals, there is an urgent need to discover new anthelmintics with distinct mechanisms of action. Extending previous work, here we screened a panel of 245 chemically-diverse small molecules for anti-parasitic activity against Haemonchus contortus—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of H. contortus using an established phenotypic assay, and the potency of select compounds to inhibit larval motility and development assessed in dose-response assays. Of the 245 compounds screened, three—designated MPK18, MPK334 and YAK308—induced non-wildtype larval phenotypes and repeatedly inhibited xL3-motility, with IC50 values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC50 values of 12.3 µM (MPK334) and 6.5 µM (YAK308), and none of the three was toxic to human liver cells (HepG2). These findings suggest that these compounds deserve further evaluation as nematocidal candidates. Future work should focus on structure–activity relationship (SAR) studies of these chemical scaffolds, and assess the in vitro and in vivo efficacies and safety of optimised compounds against adults of H. contortus.