Purpose: Curcumin exerts its anti-cancer effects, partly by targeting special microRNAs, in human cancers. MiR-21 is a key oncomirin carcinogenesis of multiple human cancers. Here, we aimed to further explore the mechanistic insight into the link betweencurcumin and miR-21 on diffuse large B-cell lymphoma (DLBCL). Materials and Methods: Quantitative real-time PCR assays were performed to assess the levels of miR-21 and Von Hippel-Lindau(VHL) mRNA. In situ hybridization assay was used for miR-21 expression visualization in lymphoma tissues. Western blot was usedfor determination of VHL protein, Ki-67, caspase-3, and cleaved caspase-3 levels. Dual-luciferase reporter assay and RNA immunoprecipitationassay were employed to confirm the direct target of miR-21. MTT assay, flow cytometric analysis, and transwell assaywere used to evaluate cell proliferation, apoptosis, and migration and invasion capacities, respectively. Results: Curcumin repressed the proliferation, migration, and invasion abilities and promoted apoptosis in SU-DHL-8 cells. Curcumininhibited miR-21 expression and curcumin exerted its anti-proliferation, anti-migration, anti-invasion, and pro-apoptosiseffects by miR-21 in SU-DHL-8 cells. VHL was a direct target of miR-21. Moreover, curcumin exerted its regulatory effects on SUDHL-8 cells by VHL. Conclusion: Curcumin exerted its anti-proliferation, anti-migration, anti-invasion, and pro-apoptosis functions, at least partly, byrepressing miR-21 and regulating VHL expression in DLBCL cell line. Our findings provided a possible molecular mechanism ofcurcumin-mediated anti-cancer effect.