Primary central nervous system lymphoma (PCNSL) is a highly aggressive brain tumor with poor prognosis if no treatment. The activation of the NF-κB (nuclear factor kappa-B) is the oncogenic hallmark of PCNSL, and it was driven by B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways. The emergence of Bruton's tyrosine kinase inhibitors (BTKis) has brought the dawn of life to patients with PCNSL. This review summarizes the management of PCNSL with BTKis and potential molecular mechanisms of BTKi in the treatment of PCNSL. And the review will focus on the clinical applications of BTKi in the treatment of PCNSL including the efficacy and adverse events, the clinical trials currently being carried out, the underlying mechanisms of resistance to BTKi and possible solutions to drug resistance.