Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcriptional differences with older age associated with decreased metabolism and telomere functions and female sex was associated with decreased interferon signaling, transcription, cell cycle, and PD-1 signaling. We discovered that the key genes for most groups strongly regulated immune function activity. Furthermore, older females were predicted to have less DLBCL progression versus older males and young females. Finally, analyses in systems biology revealed that JUN and CYCS signaling were the most critical factors associated with tumor progression in older and male patients. We identified important molecular perturbations in DLBCL that were strongly associated with age and sex and were predicted to strongly influence tumor progression.