Double-expressor diffuse large B-cell lymphoma (DLBCL) with 17p deletion is an aggressive and refractory disease. Immune checkpoint blockade and epigenetic drugs have been widely used, but the efficacy of different combined applications varied. We report a case with "double-expressor" DLBCL treated with a combined regimen which consisted of programmed cell death protein 1 (PD-1) inhibitor, DNA methyltransferase inhibitor (DNMTi), and histone deacetylase inhibitor (HDACi). A 50-year-old man presented with a 6-month history of hoarseness, and 10 days of progressive shortness of breath was diagnosed of DLBCL, stage IV. The patient failed to respond to the 1st line (R-EPOCH: rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone), 2nd line (R-EPOCH + lenalidomide + ibrutinib), and a 3rd line chemotherapy combined with PD-1 inhibitor (sintilimab), decitabine, and GDP (gemcitabine, DDP, and dexamethasone). Surprisingly, patient's condition was improved after treatment with PD-1 inhibitor in combination with DNMTi/HDACi. Restaging PET revealed dramatically radiological response.