The primary uterine diffuse large B cell lymphoma (DLBCL) is an extremely rare and poorly studied disease. Clinically, the treatment options and management for primary uterine DLBCL cases have not been standardized. Here, we reported the first clinical practice of proteomics-guided precision treatment in a primary uterine DLBCL patient. The case, a 55-year-old female, was pathologically confirmed as non-specific, germinal center B-cell-like phenotype. Oncologists initially recommended an R-CHOP regimen. After LC-MS/MS-based proteomic analysis for the Formalin-fixed paraffin-embedded (FFPE) tissue samples from the patient, the overexpressed JAK1, STAT3, BTK, and NFKB2 were identified and compared with in-house protein expression reference ranges established using 4,500 para-cancer tissues, which indicated activation of the JAK-STAT3 and BCR signaling pathways. These results suggested an increased risk of R-CHOP resistance and a possibility of targeting BTK. Thus, the oncologist optimized the treatment plan by combining R-CHOP and BTK inhibitor (Zanubrutinib). Expectably, after 4 cycles, the patient received a PET-CT evaluation, which revealed no signs of hypermetabolic tumor recurrence and achieved complete remission (CR). By far, the patient has remained stable to date, achieving a total disease-free survival (DFS) time exceeding 12 months. Collectively, this case exemplifies the emerging role of proteomics in guiding oncological treatment, showcasing how precision medicine can enhance therapeutic outcomes in clinical oncology.