Aumolertinib is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), although it has been administered for the treatment of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). However, it is unclear whether aumolertinib combined with ionizing radiation (IR) has potential therapeutic effects in treating brain metastases (BM) tumors from NSCLC. This study explored the anti-tumor effects of aumolertinib combined with IR in epidermal growth factor receptor mutated (EGFRm) NSCLC BM tumors. First, we established a xenograft model of NSCLC BM tumors in BALB/c nude mice and assessed the anti-tumor effects of this combination. Furthermore, we examined the concentrations of aumolertinib in brain tissue and blood using liquid chromatography-mass spectrometry (LC-MS); after that, we used CCK-8, colony formation, flow cytometry assay, and immunofluorescence staining to detect the effects of aumolertinib combined with IR upon PC-9 and NCI–H1975 cells, such as cell proliferation, survival, apoptosis, cycle distribution, the situation of DNA damage, and the expression levels of relevant proteins which were detected via western blotting; finally, we chose a clinical case with which to explore the clinical benefits to the EGFRm NSCLC BM patient after the treatment of the aforementioned combination. The experiments of NSCLC BM tumor animal models demonstrated that the combination enhanced the therapeutic effects and increased the intracranial accumulation of aumolertinib; the combination can inhibit cell proliferation and survival, delay the repair of DNA damage, and increase the rates of cell apoptosis and aumolertinib abrogated G2/M phase arrest, which the IR induced; the clinical study verified that the combination demonstrated better patient benefits. In conclusion, our study demonstrated that combining aumolertinib and IR has promising anti-tumor effects in EGFR-mutant NSCLC and that this combined treatment modality may be employed as a potential therapeutic strategy for EGFR-mutant NSCLC BM patients clinically.