This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy. We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis. This  found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions.