Background: Children 6-59 months with uncomplicated severe and moderate acute malnutrition (SAM and MAM) are treated in separate programs with different food products. The aim of this research was to generate evidence on a simplified, combined SAM and MAM approach, using a mid-upper arm circumference (MUAC)-based dosage protocol. Methods: An analysis of routine program data of 5,518 children from five countries estimated the energy requirements of children recovering from acute malnutrition to develop a MUAC-based combined protocol. A cluster-randomized controlled trial in Kenya and South Sudan tested if the combined protocol was as effective at recovering children but more cost-effective than standard treatment. A secondary analysis explored outcomes in children with low weight-for-age (WAZ <-3.0) and/or MUAC <11.5 cm. Results: In the routine program analysis, energy requirements for children with a MUAC <12.5 cm could be met or exceeded by 1,000 kcal/day. In the trial, 2,488 children completed treatment; 981 (76.3%) on the combined protocol and 884 (73.5%) on the standard protocol recovered. The combined protocol was non-inferior to standard treatment at a 10% non-inferiority margin, with a risk difference of 0.03 (95% CI -0.05 to 0.10, p=0.52) in per-protocol analysis, adjusted for country, age and sex. The amount of ready-to-use food to fully recover a child admitted with SAM was less in the combined protocol (122 versus 193 sachets), and the combined protocol cost $123 less per child recovered ($918 vs 1,041). Children with a WAZ <-3.0 or a MUAC <11.5 cm respond similarly to the combined protocol or standard treatment. Conclusion: A simplified, combined protocol for SAM and MAM achieves similar recovery as standard treatment and improves cost-effectiveness. Improving cost-effectiveness may enable health programs to treat more children. Adding WAZ <-3 as an admission criterion to simplified programs may help target high-risk children who benefit from treatment.