Preclinical and/or clinical studies have demonstrated the potential of Ivermectin (IVM) for malaria control. In order to improve its antiplasmodial activity and build on previous knowledge, we have designed a third generation of hybrid molecules in which selected pharmacophores were appended to the IVM macrolide, while retaining one or both sugar moieties at the C-13 position. Moreover, we synthesized IVM hybrids that contain structural features of potent IVM metabolites. The evaluation of the in vitro antiplasmodial activity of these compounds against Plasmodium berghei pre-erythrocytic stages and Plasmodium falciparum erythrocytic stages identified molecules that displayed enhanced activity against the latter when compared to IVM. Additionally, two IVM intermediates and one IVM hybrid retained the insecticidal activity of the parental molecule, clarifying the contribution of the sugar moieties to this feature. Altogether, these results provide key structure-activity relationships to guide the rational design of new generations of IVM hybrids.