Purpose: Brain tumors, whether primary or secondary, have limited information about proteomic changes despite advances in the understanding of the driver gene mutations and heterogeneity within tumor cells. The purpose of this study is to distinguish primary and secondary brain tumors based on proteomics. Experimental Design: We assembled the most common primary tumors as follows: gliomas from WHO grade II to IV with or without IDH1 mutations; and BrMs with a wide range, including lung cancer (L.C), breast cancer (B.C), ovarian cancer (O.C), and colorectal cancer (C.C). A total of 29 tissue samples were analyzed by label free quantitative mass spectrometry-based proteomics. Results: In total, 8,370 protein groups were identified, and approximately 4,000 quantified protein groups were adopted for further analysis. Proteomic analysis of metastatic tumors reveals conserved features across multiple cancers. While proteomic heterogeneities were found for discriminating low- and high-grade of gliomas, as well as IDH1 mutant and wild-type gliomas. And distinct pathway-level differences among these two types of brain malignancies were revealed. The characteristic pathways of BrMs focused on proliferation and immunomodulation after colonizing the brain, whereas invasion processes were notably activated in gliomas. Conclusions and Clinical Relevance: We elucidated an extensive proteomic landscape of BrMs and gliomas, providing information for the development of potential therapeutic and diagnostic strategies for type-specific brain tumors.