Malaria remains one of the major health problems in the world. In this work, a series of squaramide tethered chloroquine, clindamycin, and mortiamide D hybrids have been synthesized to assess their <i>in vitro</i> antiplasmodial activity against 3D7 (chloroquine-sensitive) and Dd2 strains of <i>Plasmodium falciparum</i>. The most active compound, a simple chloroquine analogue, displayed low nanomolar IC<sub>50</sub> value against both strains (3 nM for 3D7 strain and 18 nM for Dd2 strain). Moreover, all molecular hybrids incorporating the hydroxychloroquine scaffold showed the most potent activities, exemplified with a chloroquine dimer, IC<sub>50</sub> = 31 nM and 81 nM against 3D7 and Dd2 strains, respectively. These results highlight the first time use of clindamycin and mortiamide D as antimalarial molecular hybrids and establish these valuable hits for future optimization.