The present study demonstrated that HK2 knockdown inactivates ERK1/2 signaling to inhibit cell proliferation, migration, and invasion but promotes cell apoptosis in vitro and in vivo by inducing E-cadherin, Bax, and caspase-3 protein expression and suppressing Ki67, N-cadherin, and Bcl-2 protein expression in DLBCL. Here, MAPK3 is linked to diffuse large B-cell lymphoma.