Background: Intracranial activity of lapatinib has been demonstrated in several studies in patients with human epidermal growth factor receptor-2 positive breast cancers (HER-2+ BC). Stereotactic radiosurgery (SRS) has been increasingly used as the local therapy for brain metastases in breast cancer patients. Increased objective response rate was observed for lapatinib plus whole brain radiotherapy (WBRT) is such patients with high toxicity. Objective: We seek to obtain clinical evidence of synergistic efficacy of lapatinib in combination with radiation therapy, in particular, SRS. Materials and methods: We carried out a comprehensive research using the following databases: PubMed; Medline; EMBASE; Cochrane library. These databases were searched until 10 June 2020. PRISMA guidelines were followed step by step for carrying out this systematic review and meta-analysis. Review Manager v 5.4 software was used for statistical evaluation of data. Results: Overall 6 studies with 843 HER-2 positive breast cancer patients (442 HER-2 amplified disease, 399 luminal B disease) were included in this systematic review and meta-analysis. A total 279 patients had received lapatinib in addition to HER-2 antibody (trastuzumab) plus/minus chemoradiotherapy, while 610 patients had received trastuzumab-based management or only chemoradiotherapy. Lapatinib-based management of BM was associated with significant increase in overall survival (HR 0.63 [0.52, 0.77], p < 0.00001). Combination of the two (trastuzumab plus lapatinib) was associated with increased survival advantage compared to each agent alone (0.55 [0.32, 0.92], p = 0.02). SRS in combination with lapatinib was associated with increased local control (HR 0.47 [0.33, 0.66], p = 0.0001). Ever use of lapatinib with SRS was associated