A series of polar dispiro-1,2,4,5-tetraoxanes were designed and synthesized via parallel synthesis to eliminate the amide linkage in the lead candidate RKA182, aiming to reduce metabolic liability. The synthesis utilized a common intermediate for divergent parallel synthesis, and a reductive amination approach was employed to prepare a library of analogues (8–24). All compounds exhibited remarkable in vitro antimalarial activity in the low nanomolar range (0.2–3.7 nM) against Plasmodium falciparum 3D7 and K1 strains, superior to chloroquine and artesunate and comparable to RKA182. Selected compounds demonstrated promising oral activity in the P. berghei ANKA mouse model, with some showing higher potency than artesunate in terms of ED90. A preliminary metabolic stability study indicated that a representative compound (18) had improved stability compared to RKA182. Combined with favorable properties such as low ClogP and high aqueous solubility, this series of tetraoxane analogues is worthy of further investigation.