Novel hydroxychloroquine (HCQ)-sugar conjugates were evaluated for their antimalarial activity against chloroquine-sensitive (Pf3D7) and multi-resistant (PfDd2) strains of Plasmodium falciparum, cytotoxicity, and hydrolytic stability. HCQ-galactose conjugate with a 1,2-orthioester linkage exhibited the highest activity against Pf3D7 (IC50 value of 0.018 ± 0.001 μg/mL). Per-O-acetyl-β-d-glucopyranosyl-HCQ exhibited the highest activity against PfDd2 (IC50 = 0.20 ± 0.02 μg/mL), while also maintaining comparable activity against Pf3D7. Orthoester-linked conjugates were gradually hydrolyzed in human serum, resulting in HCQ release, which may contribute to their high activity. Glycosidic bond-linked conjugates showed high hydrolytic stability, retaining a certain level of activity, possibly without releasing HCQ. Toxicity assessments using the BHK21 cell line indicated significantly lower cytotoxicity for all HCQ-sugar conjugates compared to HCQ.