One of the key challenges in developing next-generation antimalarials lies in ensuring efficacy across multiple stages of the parasite's life cycle while maintaining safety, particularly for vulnerable populations such as young children and pregnant women. Given the complex dynamics of parasite biology, including its 48-hour erythrocytic cycle and sequestration in tissues, the development of a single-dose medicine with prolonged activity presents a formidable task. Our study addressed this challenge by exploring the potential of covalent kinase inhibitors, a strategy previously unexplored in the context of malaria. Given the success of covalent kinase inhibitors in oncology, we believe this strategy could be harnessed in the malaria field. Though one-third of approved targeted covalent inhibitors target infectious diseases, this does not include the greatest parasitic killer. The increased duration of action attributed to an irreversible mechanism and increased selectivity can allow for smaller and less frequent dosing, which may improve patient compliance-a significant issue in the treatment of malaria. The ability of covalent inhibitors to evade mutation events which lead to resistance also make them ideal candidates for malaria eradication. Through high-resolution structural elucidation and molecular modeling, we identified a non-conserved cysteine residue (Cys368) proximal to the ATP pocket of PfCLK3 as a suitable target for covalent inhibition. Subsequent synthesis and evaluation of covalent analogues revealed improved parasiticidal potency, selectivity over the human kinome, and enhanced cell viability profiles compared to the parent molecule, TCMDC-135051 (1). Importantly, our findings suggest that covalent binding mechanisms offer pharmacodynamic and parasiticidal properties conducive to the development of a single-dose cure for malaria.