Focal adhesion (FA) proteins have been associated with transformation, migration, metastasis, and poor outcome in many neoplasias. We previously showed that these proteins were inhibited by E7123, a new celecoxib derivative with antitumor activity, in acute myeloid leukemia. However, little is known about FAs in diffuse large B cell lymphoma (DLBCL). This paper aimed to determine whether E7123 was effective against DLBCL and whether FAs were involved in its action. We evaluated the cytotoxicity and mechanism of action of E7123 and celecoxib in DLBCL cell lines. We also assessed the E7123 in vivo activity in a DLBCL xenograft model and studied FA signaling in primary DLBCL patient samples. We found that E7123 showed higher antitumor effect than celecoxib against DLBCL cells. Its mechanism of action involved deregulation of FA, AKT, and Mcl-1 proteins, a pathway that is activated in some patient samples, apoptosis-inducing factor release and induction of caspase-independent cell death. Moreover, E7123 showed suppression of in vivo tumor growth. These findings indicate that E7123 is effective against DLBCL in vitro and in vivo, with a mechanism of action that differs from that of most current therapies for this malignancy. Our results support further preclinical evaluation of E7123.