Schistosomiasis, caused by Schistosoma spp. flatworms, is some of the most prevalent tropical diseases worldwide. Although recent control efforts have significantly reduced morbidity and mortality in many regions, major challenges persist in endemic areas. Metal complexes are important assets in the pipeline for designing new anti-infective agents because they can engage molecular targets that are inaccessible to their purely organic counterparts. This property motivated our interest in targeting adult Schistosoma mansoni worms residing in the mesenteric veins using antiparasitic Pt(II) and Pd(II) complexes containing mefloquine (MQ) in their coordination spheres. To evaluate the capacity of Pt(II) and Pd(II) agents to reach blood parasites and to deliver MQ payload, an efficient synthesis of aqueous-stable, MQ–metal complexes with the general formula [M(II)(L)(MQ)]PF6 was developed. These metallic complexes have preferentially target pathogens circulating in the bloodstream rather than host cells, exhibited potent in vitro antiparasitic activity, low apparent intrinsic clearance in mouse liver microsomes, by binding and inhibiting thioredoxin-glutathione reductase (SmTGR), a molecular target not affected by MQ alone. Notably, a bidentate coordination of MQ was essential for achieving potent antiparasitic effect, and importantly, the stability of the complexes.