Background Central nervous system lymphoma (CNSL) is aggressive, and treatment with Bruton tyrosine kinase (BTK) inhibitors (BTKis) plays a key role. For this systematic review and meta-analysis, the authors evaluated BTKis for the treatment of primary CNSL (PCNSL) and secondary CNSL (SCNSL).Methods By May 1, 2025, the authors conducted a systematic search of databases, including PubMed, EMBASE, etc. Included studies were those that investigated BTKi-treated CNSL and analyzed the overall response rate (ORR) as well as the complete response (CR) and partial response (PR) rates using systematic review and meta-analysis software.Results Forty studies (935 patients) were included in the meta-analysis. The pooled ORR and CR and PR rates were 73%, 49%, and 28%, respectively. The pooled ORR and CR rates for BTKi monotherapy were 60% and 34%, respectively; whereas the rates for BTKi plus chemotherapy or immunochemotherapy were 79% and 55%, respectively. For PCNSL, the pooled ORR and PR rates were 73% and 49%, respectively. For SCNSL, the pooled ORR and CR rates reached 75% and 53%, respectively. Among patients with PCNSL, zanubrutinib achieved pooled ORR and CR rates of 85% and 54%, respectively. Ibrutinib had pooled ORR and CR rates of 67% and 46%, respectively; whereas orelabrutinib demonstrated pooled ORR and CR rates of 70% and 59%, respectively. For SCNSL, zanubrutinib achieved pooled ORR and CR rates of 77% and 62%, respectively; whereas ibrutinib achieved rates of 72% and 54%, respectively. Hematologic toxicities and transaminase increases were grade 3-5 toxicities according to common toxicity criteria.Conclusions The combination of BTKis with traditional chemotherapy or immunochemotherapy offers superior response rates compared with BTKis alone, and the safety profile is acceptable. Efficacy varies by BTKi type and should be selected based on patient condition. Specifically, for PCNSL, the response rates of zanubrutinib and obinutuzumab are better; for SCNSL, there is a minimal difference in efficacy among the various BTKis; and, overall, regardless of whether it is PCNSL or SCNSL, the off-target effects and side effects of covalent BTKis (zanubrutinib, obinutuzumab), except for ibrutinib, have improved.