Pediatric acute myeloid leukemia (AML) exhibits distinct genetic characteristics, including unique driver alterations and mutations with prognostic and therapeutic significance. Emerging rare, recurrent genetic abnormalities and their associations with outcomes emphasize the need for high-throughput molecular diagnostic tools. Whole genome sequencing (WGS) reliably detects key AML biomarkers such as structural variants, mutations, and copy number alterations. Whole transcriptome sequencing (WTS) complements WGS by uncovering oncogene expression patterns, allele-specific expression, and gene expression signatures. In this study, we describe an integrated WGS and WTS clinical workflow for routine pediatric AML diagnosis and present a systematic evaluation of its application compared to conventional cytogenetics and standard molecular diagnostic methods. Our findings demonstrate that the integrated WGS and WTS (iWGS-WTS) approach improves the identification of clinically relevant genetic alterations, enhancing precise disease classification and risk assessment. Moreover, with advancements in workflow and bioinformatics pipelines, the testing turnaround time can be optimized to meet the demands of clinical decision-making, positioning iWGS-WTS as a practical and superior alternative to traditional diagnostic methods in pediatric AML management.