Extreme weather conditions lead to significant imbalances in crop productivity, which in turn affect food security. Flooding events cause serious problems to many crop species such as wheat. Although metabolic readjustments under flooding are important for plant regeneration, underlying processes remain poorly understood. Here, we investigated the systemic response of wheat to waterlogging using metabolomics and transcriptomics. A 12-day exposure to excess water triggered nutritional imbalances and disruption of metabolite synthesis and translocation, reflected by reduction of plant biomass and growth performance. Metabolic and transcriptomic profiling in roots, xylem, and leaves indicated anaerobic fermentation processes as a local response occurring in roots. Differentially expressed genes and ontological categories revealed that carbohydrate metabolism plays an important role as a systemic response. Analysis of the translocation rate of specific compounds in the xylem showed how waterlogging alters the composition of xylem exudates and thus the root to shoot communication. Interestingly, among all metabolites determined in our study, alanine was the most abundant transported in the xylem. Our results suggest an important role of this amino acid not only as amino-nitrogen source but also as the major root-to-shoot translocated and systemically acting metabolite crucial for balancing C/N between roots and shoots during waterlogging. The relevance of this study relies on the basis to characterize the important role of alanine as Highlight Metabolic and transcriptomic changes in wheat highlight alanine as the major root-to-shoot translocated and systemically acting metabolite crucial for balancing C/N between roots and shoots.