Diffuse large B-cell lymphoma (DLBCL) is a prevalent subtype of non-Hodgkin's lymphoma (NHL). Ferroptosis is a novel form of cell death involved in multiple tumor development. However, the relationship between ferroptosis-related genes and DLBCL has not been extensively studied. The GSE95290 dataset was downloaded from the Gene Expression Omnibus (GEO) database and merged with genes associated with ferroptosis to screen differentially expressed genes (DEGs). Hub genes were identified by constructing a protein-protein interaction (PPI) network. The messenger RNA (mRNA) expressions of hub genes were subsequently detected in vitro using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). The impact of voltage dependent anion channel 1 (VDAC1) on the proliferation, apoptosis, and ferroptosis of DLBCL was evaluated using Cell Counting Kit-8, flow cytometry, and relevant ferroptosis assays, respectively. Six highly expressed hub genes were identified, all of which could be used as diagnostic biomarkers for DLBCL. In vitro studies revealed that suppressing VDAC1 expression inhibited DLBCL cell proliferation and promoted apoptosis. Furthermore, knockdown of VDAC1 promoted ferroptosis in DLBCL cells and xenograft tumor models, resulting in elevated levels of malondialdehyde (MDA) and iron and increased protein levels of Acyl-CoA synthetase long-chain family 4 (ACSL4) and cyclooxygenase-2 (COX2). Conversely, glutathione (GSH) and superoxide dismutase (SOD) levels were reduced, accompanied by decreased protein levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain1 (FTH1). VDAC1 knockdown induces ferroptosis in DLBCL, which provides new insights into the pathogenic mechanisms of DLBCL.