Widespread resistance of parasitic nematodes to existing anthelmintics has created an urgent need for new drugs with distinct modes of action. Haemonchus contortus provides a robust experimental model for such drug-discovery efforts, underpinned by the availability of extensive multi-omics resources. Understanding how candidate small molecules interact with parasite proteins is critical for rational drug development. Here, we combined global protein profiling with Proteome Integral Solubility Alteration (PISA) analysis to investigate the molecular responses of H. contortus to two novel compounds, WEHI-2050192 and WEHI-2050920, with known in vitro activity against this parasite. Quantitative proteomics revealed limited but consistent changes in protein abundance in adult female worms following drug exposure, with the transthyretin-like protein TTR-52 being markedly downregulated upon treatment. PISA analysis identified compound interactions with TTR-52 and several other proteins involved in ribosomal function, cytoskeletal organisation and vesicular trafficking. Notably, TTR-52, an excreted/secreted protein implicated in immune modulation and developmental regulation in nematodes, was identified by both methods as a shared target across different developmental stages of the parasite. These findings suggest that TTR-52 represents a functionally relevant molecular marker and potential drug target. This study demonstrates the value of integrating protein profiling with PISA to infer mode-of-action signatures and to prioritise candidate targets for anthelmintic discovery.