The management of (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-R's heightened reliance on host lipids. Here, we report that LD-R-infection in mice promotes fluid-phase endocytosis in the host macrophages, selectively accumulating neutral lipids while excluding oxidized-low-density lipoprotein (LDL). LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness toward Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.