(1)Wood production in fast-growing Eucalyptus grandis trees is highly dependent on both potassium (K) fertilization and water availability but the molecular processes underlying wood formation in response to the combined effects of these two limiting factors are still unknown (2)E. grandis trees were submitted to four combinations of K-fertilization and water supply. Weighted gene co-expression network analysis (WGCNA) and MixOmics-based co-regulation networks were used to integrate xylem transcriptome, metabolome and complex wood traits. Functional characterization of a candidate gene was performed in transgenic E. grandis hairy roots. (3)This integrated network-based approach enabled us to identify meaningful biological processes and regulators impacted by K-fertilization and/or water limitation. It revealed that modules of co-regulated genes and metabolites strongly correlated to wood complex traits are in the heart of a complex trade-off between biomass production and stress responses. Nested in these modules, potential new cell wall regulators were identified as further confirmed by the functional characterization of EgMYB137. (4)These findings provide new insights into the regulatory mechanisms of wood formation under stress conditions pointing out both known and new regulators co-opted by K-fertilization and/or water limitation that may potentially promote adaptive wood traits.