Malaria remains a global health challenge, necessitating novel therapeutic approaches. Here, we explore the role of the sphingolipid metabolism in Plasmodium infection. We focus on the enzyme acid sphingomyelinase (Asm), which hydrolyzes sphingomyelin to ceramide, a structural but also bioactive membrane molecule. We demonstrate induction of Asm activity in infected mice, leading to elevated ceramide levels in infected red blood cells. Pharmacological inhibition of Asm with the functional inhibitor amitriptyline in Plasmodium yoelii (Py)- and Plasmodium berghei ANKA (PbA)-infected mice significantly reduces parasitemia and mitigates disease-associated pathology. Amitriptyline treatment also reduces T cell activation, preserving blood-brain barrier integrity upon PbA infection. Remarkably, we observe inhibition of Plasmodium falciparum growth in vitro upon exposure to amitriptyline. Mechanistically, we elucidate that amitriptyline impedes intra-erythrocytic parasite development, due to a reduced glucose uptake and thereby interfering with the spreading of blood-stage Plasmodium parasites. Our findings highlight the therapeutic promise of targeting sphingolipid metabolism to combat Plasmodium infections.