FER, an intracellular tyrosine kinase, is ubiquitously expressed in malignancies. However, the regulatory mechanisms of FER in diffuse large B-cell lymphoma (DLBCL) remain elusive. Here, we found that FER was upregulated in DLBCL, leading to unfavorable outcomes and increased tumorigenesis, as well as resistance to chemotherapy. While exposing cells to the FER inhibitor E260, cell proliferation and tumor growth were repressed. Moreover, greater tumor suppression resulted from combining exosome-E260 with chemotherapeutics compared with the suppression achieved by monotherapy. Mechanistically, E260 restored the activity of Hippo signaling by inhibiting AJUBA, resulting in YAP cytoplasmic sequestration. Furthermore, circulating exosomal FER may act as an indicator for the diagnosis and progression of DLBCL. In summary, FER could serve as a prognostic indicator and therapeutic target in DLBCL. Additionally, the application of exosomes in diagnosis or treatment may open up novel avenues for cancer therapy.