To evade the possible toxicity associated with the formation of quinone-imine metabolite in amodiaquine (AQ), the <i>para</i>-hydroxyl group was replaced with a -F atom, and the resulting 4'-fluoro-amodiaquine (FAQ) was hybridized with substituted pyrimidines. The synthesized FAQ-pyrimidines displayed better <i>in vitro</i> potency than chloroquine (CQ) against the resistant <i>P. falciparum</i> strain (Dd2), exhibiting up to 47.3-fold better activity (IC<sub>50</sub>: 4.69 nM) than CQ (IC<sub>50</sub>: 222 nM) and 2.8-fold better potency than artesunate (IC<sub>50</sub>: 13.0 nM). Twelve compounds exhibited better antiplasmodial activity than CQ against the CQ-sensitive (NF54) strain. Two compounds were evaluated <i>in vivo</i> against a <i>P. berghei</i>-mouse malaria model. Mechanistic heme-binding studies, computational docking studies against <i>Pf</i>-DHFR and <i>in vitro</i> microsomal stability studies were performed for the representative molecules of the series to assess their antimalarial efficacy.