ObjectiveTo determine time and cost differences between one- and two-step injectable artesunate formulations for treatment of severe malaria and compare their safety and treatment outcomes.MethodsWe conducted an open-label randomized clinical trial at hospitals in Kinshasa, Democratic Republic of the Congo and Korogwe, United Republic of Tanzania in patients aged 3 months to 16 years with severe malaria. We randomly allocated patients to a new one-step injectable artesunate formulation or the conventional two-step formulation. After discharge, patients were followed for 4 weeks. The main outcomes evaluated were time and cost of administering treatment, and clinical and pharmacodynamic effects.FindingsBetween 7 June 2022 and 11 August 2023, 200 patients were randomized (1:1) to either the one-step or two-step arm. Mean time to administer artesunate was 2 min 22 s (standard deviation, SD: 50 s) in the one-step arm and 3 min 41 s (SD: 95 s) in the two-step (P-value: < 0.0001). Mean cost of syringes and needles used per patient was 0.53 (SD: 0.13) United States dollars (US$) in the one-step arm versus US$ 0.84 (SD:  0.22) in the two-step (P-value: 0.0001). Parasite clearance half-lives were 2.1 h (SD: 0.9) in the one-step arm and 2.0 h (SD: 0.8) in the two-step (P -value: 0.173). Severe adverse events occurred in one patient in each arm (P -value: 1.000), while 242 and 229 ungraded adverse events occurred in the one- and two-step arms, respectively (P -value: 0.549).ConclusionIn children with severe malaria, one-step injectable artesunate was quicker and cheaper to administer and had equivalent safety and efficacy compared with the conventional formulation.