Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Transcriptomic and genetic characterization of DLBCL have increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constrains of lymphoma growth; supporting the rationale for implementing DNA hypomethylating agents in selected DLBCL patients. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in pre-clinical models. This novel classification provides a roadmap for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.