Growth hormone (GH) imposes pleiotropic effects on human tissues by coordinating growth, facilitating metabolic, cardiovascular, immune, and neuroendocrine systems, and governing the aging process. Growth hormone deficiency (GHD) is estimated to occur in 2.5% of children and may present with age-dependent symptoms: hypoglycemia, jaundice in infancy, and poor growth in childhood. This study attempts to define the GH-immune landscape and its complex molecular drivers at the systems level. Integrative statistical analysis of multi-omic data from blood of 52 children with short stature before and after a GH stimulation test showed significant, concordant changes imposed by GH across the whole genome, metabolome, and inflammatory proteome. These changes involved signaling molecules along the GH/IGF axis, the JAK-STAT pathway, cytokines, and GH-induced nitrogen metabolism. Interferon signaling network drivers were correlated significantly with GHD demonstrating the prominent role of interferon at the nexus of the endocrine, immune and metabolic systems.