Background: Malnutrition is one of the main health problems facing children under five years of age in developing countries. Undernutrition imposes significant costs on the Ethiopian economy as well as impacting the well-being of the society. The aim of this study was to assess determinants of acute malnutrition among children aged 6-59 months attending public health facilities in Gambella Town, Southwest Ethiopia, 2019. Methods: An institution-based unmatched case-control study was conducted among children aged 6-59 months with and without acute malnutrition visiting public health facilities in Gambella town from June 7 to July 21, 2019. Data were collected using an interviewer-administered structured questionnaire and anthropometric measurement was done by standardized calibrated instruments. The collected data were entered onto EpiData™ version 3.1 and then exported to SPSS version 20 for analysis. Both bivariate and multivariable logistic regression analyses were used to identify determinants of acute malnutrition. Statistical significance was declared at P-value of <0.05. Results: A total of 342 children (114 cases and 228 controls) with mother/care giver pair were interviewed making the response rate 100%. Maternal education (AOR=2.55, 95%CI: 1.02-6.37), birth order of the child (AOR=3.65, 95%CI: 1.21-11.03), number of under-five children in the family (AOR=3.40, 95%CI: 1.03-11.22), immunization status (AOR=4.60, 95%CI: 1.51-13.99), IYCF counseling (AOR=6.02, 95%CI: 2.91-12.46), time of initiation of breastfeeding after birth (AOR=2.43, 95%CI: 1.14-5.17), and diarrhea in the last two weeks preceding the survey (AOR=2.74, 95%CI: 1.32-5.68) were significantly associated with acute malnutrition among children aged 6-59 months. Conclusion: This study identified the basic, underlying, and immediate determinants of acute malnutrition among children aged 6-59 months. Multisectoral collaboration to improve women's education, IYCF counseling, environmental sanitation, vaccination completion, and prompt seeking of diarrhea treatment to reduce acute malnutrition is required.