Malaria is one of the most prevalent infectious disease caused by parasites from Plasmodium genus. In this work, we investigated the antiplasmodial and cytotoxic activity of chalcogen-phosphoranes derivatives against sensitive (3D7 strain) and resistant (Dd2, TM90C6B, 3D7R_MMV848, Dd2R_DSM265) P. falciparum strains. Briefly, seleno-phosphoranes showed greater IC50 values (4.2 to >10 µM) when compared with the thio-phosphoranes analogs (0.7 to 1.9 µM). Electron-withdrawing substituents lead to analogs with enhanced antiplasmodial potency compared with electron-donating substituents. The most potent derivative had sulfur and bromide as substituent. This compound was evaluated against resistant strains of P. falciparum (e.g., Dd2, TM90C6B, 3D7R_MMV848, Dd2R_DSM265) and showed no cross-resistance with the gold-standard antimalarials. Hence, thio-phosphoranes showed reasonable potency against sensitive and resistant strains (RI <3) as well as an attractive selectivity index (>20) when tested against HepG2 and HEK293 cells. Our findings indicated that the phosphoranes derivatives are attractive hits for an antimalarial drug discovery program.