Antimalarial chemotherapy is crucial for reducing morbidity, mortality, and drug resistance, and is the cornerstone of malaria control. Existing antimalarial drugs act at different stages of the parasite’s life cycle. These drugs range from classic agents such as chloroquine and quinine to newer artemisinin derivatives. They include tissue schizonticides, blood schizonticides, gametocytocides, and sporontocides. Artemisinin and its derivatives are the most effective and fastest-acting treatment against drug-resistant Plasmodium falciparum, achieving rapid parasite clearance and reducing transmission potential. Other key drugs include mefloquine, halofantrine, proguanil, sulfadoxine–pyrimethamine, atovaquone–proguanil, tetracyclines, clindamycin and azithromycin. Each of these drugs has a specific mechanism of action, pharmacokinetics, efficacy, safety profile and contraindications. Rational drug combinations and adherence to national treatment guidelines are essential for managing resistance, ensuring safety in vulnerable populations such as children and pregnant women, and optimising therapeutic outcomes in cases of both uncomplicated and severe malaria.