Background: Admission criteria that treat children with low mid-upper-arm circumference (MUAC), and low weight-for-height z-score (WHZ) are not aligned with the evidence on which children are at risk of mortality. An analysis of community-based cohort data from Senegal found that a combination of weight-for-age (WAZ) and MUAC criteria identified all children at risk of near-term death associated with severe anthropometric deficits. This study will address whether children with WAZ <−3 but MUAC ≥125 mm benefit from therapeutic feeding with ready-to-use therapeutic foods (RUTF) and whether a simplified protocol is non-inferior to the weight-based standard protocol. Methods: This is a prospective individually randomized controlled 3-arm trial conducted in the Nara health district in Mali. Children aged 6–59 months presenting with MUAC ≥125 mm and WAZ <−3 will be randomized to (1) control group receiving no treatment, (2) simplified treatment receiving 1 sachet of RUTF daily until WAZ ≥−3 for 2 visits, (3) standard treatment receiving RUTF according to WHZ category: (a) WHZ <−3 receive 200 kcal/kg/day until WHZ ≥−2 for 2 visits, (b) WHZ ≥−3 but <−2 receive 1 sachet daily until WHZ ≥−2 for 2 visits or (c) WHZ ≥−2 receive no treatment. All children will be followed up first fortnightly for 12 weeks and then monthly until 6 months post-enrolment. The primary endpoint will be measured at 2 months with the primary outcome being WAZ as a continuous measure. Other outcomes include other anthropometric measurements and a secondary endpoint will be observed at 6 months. A total of 1397 children will be recruited including 209 in the control and 594 in both the simplified and standard arms. The sample size should enable us to conclude on the superiority of the simplified treatment compared to no treatment and on the non-inferiority of the simplified treatment versus standard treatment with a margin of non-inferiority of 0.2 WAZ. Discussion: This trial aims to generate new evidence on the benefit of treating children with WAZ <−3 but MUAC ≥125 mm in order to guide the choice of admission criteria to malnutrition treatment and build evidence on the most efficient treatment protocol. Trial registration: This trial was registered at ClinicalTrials.gov: NCT05248516 on February 21, 2022.