Background: Central nervous system lymphoma (CNSL) is considered an aggressive lymphoma with a poor prognosis. Studies investigating CNSL have shown that chimeric antigen receptor (CAR) T-cell therapy has demonstrated an effective response in limited sample sizes. Therefore, we conducted this systematic review and meta-analysis to clarify the sustained efficacy and factors associated with the sustained efficacy of CAR T-cell therapy in the treatment of CNSL. Methods: We searched studies from PubMed, Embase, Medline, and the Cochrane Center Register of Controlled Trials up to July 2023. Studies that included individual data on the duration of response (DoR) after receiving CAR T-cell therapy were enrolled. Pooled response rates were calculated using fixed-effects or random-effects models. Subgroup analysis was performed to analyze the heterogeneity, and a Cox regression model was performed to identify the factors associated with sustained efficacy. Results: In total, 12 studies including 69 patients were identified and included in this meta-analysis. The pooled relapse rate was 45% [95% CI 35, 56]. Subgroup analyses of relapse rates revealed that CAR T-cells using the CD28/4-1BB domain (CD28/4-1BB vs. CD28 vs. 4-1BB, p = 0.0151), parenchymal or leptomeningeal involvement (parenchymal or leptomeningeal vs. both parenchymal and leptomeningeal, p < 0.0001), and combined treatment with CAR T-cell therapy [Autologous stem cell transplantation (ASCT) plus CAR T-cell therapy vs. CAR T cells with maintenance therapy vs. CAR T-cell therapy alone, p = 0.003] were associated with lower relapse rates in patients. Time-to-event endpoints were assessed using reconstructed individual patient survival data to explore key modulators of DoR. Partial response status at CAR-T infusion and the use of ASCT plus CAR T-cell therapy were associated with longer DoR at the multivariate level, with hazard ratios of 0.25 and 0.26, respectively. Conclusion: CAR T-cell therapy shows promising and sustained efficacy in CNSL patients. However, further prospective large-scale studies are needed to assess these effect modifiers to optimize patient selection and improve the sustained efficacy of CAR T-cell therapy in the treatment of CNSL. Systematic review registration: https://clinicaltrials.gov/, identifier PROSPERO CRD42023451856.