Background: Liquid biopsy has played a unique role in long-term surveillance of brain metastasis in non-small cell lung cancer (NSCLC), due to the inaccessibility of solid metastatic biopsies. T cell-mediated immunity is critical in the oncogenesis and metastasis of NSCLC, and sequencing in T cell receptor (TCR) provides a robust method to quantify T cell diversity. Therefore, we aimed to explore the alteration of TCR through liquid biopsy before and after radiotherapy of NSCLC brain metastases. Methods: Thirty NSCLC patients with brain metastases receiving brain radiotherapy were enrolled in this study. Cerebrospinal fluid (CSF) and peripheral blood were collected at baseline, 24 hours (T0) and 28 days (T28) after treatment. TCR sequences were identified by high-throughput sequencing in both compartments. Results: At baseline, dimension reduction analysis identified distinct signatures of V and J gene recombination in blood and CSF TCR sequences. Throughout treatment, both compartments experienced a TCR diversity decrease, however, the degradation of low-abundance clones and the expansion of emerging clones might be two separate processes underwent in blood and CSF, respectively. Diversity changes in blood were possibly related to pulmonary responses, while the increase of maximal clone abundance in CSF might indicate a favorable intracranial response. Superior blood TCR diversity at T28 against baseline was associated with longer OS (HR = 5.700, p = 0.039). Patients with increase of maximal clone abundance ≥ 50 in CSF also had a better intracranial PFS (HR = 8.320, p = 0.011). The predictive effects of these markers were independent of other clinical factors in multivariate Cox analysis. Conclusions: CSF and peripheral blood were independent compartments showing disparate TCR signatures. Longitudinal surveillance of both compartments could be a promising method to predict clinical outcomes for NSCLC patients with brain metastases.