The resistance of conventional antimalarial drugs against the malarial parasite continues to pose a challenge to control the disease. The indiscriminate exploitation of the available antimalarials has resulted in increasing treatment failures, which urges on the search for novel lead molecules. Artemisinin-based combination therapy (ACT) is the current WHO-recommended first-line treatment for the majority of malaria cases. Hybrid molecules offer a newer strategy for the development of next-generation antimalarial drugs. These comprise molecules, each with an individual pharmacological activity, linked together into a single hybrid molecule. This approach has been utilized by several research groups to develop molecules with potent antimalarial activity. In this review, we provide an overview of the pivotal roles of quinoline- and endoperoxide-based hybrids as inhibitors of the life-cycle progression of Plasmodium. Based on the exhaustive literature reports, we have collated the structural and functional analyses of quinoline- and endoperoxide-based hybrid molecules that show potency equal to or greater than those of the individual compounds, offering an effective therapeutics option for clinical use.