Childhood illnesses from infectious diseases in low- and middle-income countries contribute substantially to the global under-five mortality. Many hospitalized children experience incomplete recovery, readmission, and post-discharge mortality despite guideline-directed care. However, targeted interventions remain elusive due to limited understanding of underlying mechanisms. In this work, we employ multiomic profiling and multivariate modeling to investigate biological drivers of inpatient and post-discharge mortality in 3,101 acutely ill children across nine sites in sub-Saharan Africa and South Asia. In a nested case-cohort (N = 1008), we generate plasma proteomics, serum metabolomics and lipidomics, stool metagenomics, and fecal pathogen data at admission and discharge. Additionally, we profile 270 geographically matched community children for biological baselines. We identify a generalizable mortality signature marked by immune, inflammatory, and metabolic dysregulation with gut dysbiosis. We show that mortality-associated signals persist from admission through discharge, indicating unresolved disease and that malnourished children show greater baseline perturbations, explaining elevated risk. We also find some children with low clinical severity display high predicted mortality risk from targeted biomarkers. Finally, we distill predictive models to a clinically feasible biomarker panel and validate our findings in an independent cohort (N = 100). By linking inpatient and post-discharge mortality to specific biological mechanisms, our findings highlight why current care can fail and demonstrate how biomarker-guided risk stratification can identify vulnerable children currently missed by clinical assessments, enabling targeted interventions to reduce mortality in low- and middle-income countries.