This study aimed to describe patient characteristics, mortality, and morbidity outcomes in children at a South African extracorporeal membrane oxygenation (ECMO) center. Fifty-seven patients required ECMO from 2018 to 2023 at the Nelson Mandela Children’s Hospital in Johannesburg; eight neonates (14%), 35 infants (61.4%) 29 days–1 year, 11 (19%) aged 1–5 years, and three (5%) over 5 years. Fifty patients received venoarterial (VA)-ECMO (88%), six (11%) received venovenous (VV)-ECMO, and one patient (2%) was converted from VV- to VA-ECMO. Nineteen (33%) required ECMO for an underlying congenital cardiac lesion; 34 (60%) for respiratory indications and four (7%) post-thoracic surgery. The overall mortality rate was 54.4% with no significant difference in survival between patients on VA-ECMO compared with VV-ECMO. Differences in patient age, sex, nutrition, and human immunodeficiency virus (HIV) status were not significantly associated with mortality. The median length of ECMO run was 14 days, with significantly longer runs in respiratory cases. The most common patient morbidities experienced on ECMO were fluid overload (92%) and infection (84%). Neurologic sequelae occurred in 40% of cases. Mechanical complications were rare. Our findings highlight that ECMO can be offered successfully despite challenges experienced in resource-limited settings. Future research should focus on specific prognostic factors of relevance to our populations.