Objective: This study aimed to explore the clinical efficacy and safety of temozolomide (TMZ) plus whole-brain radiotherapy (WBRT) in the treatment of intracranial metastases. Subjects and Methods: A total of 72 patients with intracranial metastases were randomly divided into observation group and control group (each n = 36). The patients of observation group received WBRT plus TMZ, while the patients of control group received WBRT. The observation index of both groups included the short-and long-term clinical efficacies, improvement of symptoms and signs, quality of life (QOL), and adverse responses. Results: After treatment, the objective remission rate in observation group (77.78%, 28/36) was evidently higher than that of in control group (47.22%, 17/36), with significant difference (P = 0.0074). However, the disease control rate in observation group (94.44%, 34/36) was only slightly higher than that of in control group (86.11%, 31/36) (P = 0.4263). Moreover, after treatment, compared to control group, observation group showed markedly better improvement in symptoms and signs, as well as QOL (P < 0.001), with significantly longer overall survival and progression-free survival (P < 0.001). Conclusion: TMZ concomitant with WBRT can increase the local control, prolong the survival time and improve the QOL of patients with intracranial metastases.