This study presents a comprehensive genomic framework for categorizing pediatric acute myeloid leukemia (pAML) by systematically classifying 887 pAML cases into 23 mutually distinct molecular categories. These categories, which include new major entities such as *UBTF* and *BCL11B*, cover 91.4% of the cohort and are associated with unique expression profiles and mutational patterns. The molecular categories show strong associations with clinical outcomes, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease (MRD). This framework, validated in two independent cohorts, forms the basis for future classification and treatment strategies for pAML. The study highlights the need for a more comprehensive classification system that reflects the unique biology of pAML, particularly in cases without category-defining alterations.This study presents a comprehensive genomic framework for categorizing pediatric acute myeloid leukemia (pAML) by systematically classifying 887 pAML cases into 23 mutually distinct molecular categories. These categories, which include new major entities such as *UBTF* and *BCL11B*, cover 91.4% of the cohort and are associated with unique expression profiles and mutational patterns. The molecular categories show strong associations with clinical outcomes, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease (MRD). This framework, validated in two independent cohorts, forms the basis for future classification and treatment strategies for pAML. The study highlights the need for a more comprehensive classification system that reflects the unique biology of pAML, particularly in cases without category-defining alterations.