Diffuse large B-cell lymphoma (DLBCL) is a malignant tumor and research on its therapeutic targets has received increasing attention. It has been reported that Leucyl-tRNA synthetase (LARS) contributes to the growth and migration of non-Hodgkin lymphoma (NHL), yet its effect on DLBCL progression remains to be elucidated. MTT and flow cytometry were carried out to determine the cellular phenotypes of DLBCL cells under LARS overexpression. The differentially expressed proteins (DEPs) were screened by mass spectrometry. ELISA, western blot, and xenograft tumor experiments were implemented to confirm the impact of LARS and the LRPPRC/HIF-1α axis on malignant progression and glycolysis. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) were applied for exploring the underlying mechanism by which LARS was regulated. LARS promoted the malignant phenotypes, such as increasing cell proliferation and inhibiting apoptosis, and enhanced abnormal glycolysis both in vitro and in vivo. Based on mass spectrometry and functional recovery experiments, we found that LARS upregulated LRPPRC expression. More importantly, overexpressing LRPPRC facilitated malignant phenotypes and glycolysis through the elevation of HIF-1α expression, which could be reversed by silenced HIF-1α. Mechanistically, LARS promoted the expression of HIF-1α by activating LRPPRC, which in turn enhanced the transcription of HK2, thereby facilitating malignant progression and abnormal glycolysis. LARS facilitated abnormal glycolysis via the LRPPRC/HIF-1α/HK2 axis, thereby promoting the malignant progression of DLBCL.