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The molecular subtype characterized by co-occurring MYD88 and CD79B alterations (MCD) represents a biologically distinct subset of diffuse large B-cell lymphoma (DLBCL) with chronic active B-cell receptor signaling and a high risk of central nervous system (CNS) involvement. The clinical impact of Bruton tyrosine kinase inhibitors (BTKi) in this subtype remains unclear. We retrospectively analyzed 155 patients with newly diagnosed DLBCL harboring genetic features consistent with the MCD subtype. At a median follow-up of 34.1 months, the estimated 3-year progression-free survival (PFS) rate was 76.1%. BTKi exposure (n = 56) was associated with significantly improved PFS compared with no BTKi exposure (3-year PFS: 93.8% vs. 66.6%, p < 0.001) and remained independently associated with improved PFS after adjustment for IPI risk (HR 0.16, p < 0.001). Overall survival did not differ significantly between groups. Notably, all 15 CNS relapse events occurred in patients who did not receive BTKi, whereas no CNS relapse was observed in the BTKi-treated group. BTKi exposure was independently associated with a markedly reduced risk of CNS relapse (HR 0.06, p = 0.002) after adjustment for CNS-IPI risk and CNS prophylaxis. These findings suggest that BTK inhibition may improve outcomes and mitigate CNS relapse in MCD DLBCL.