Colorectal cancer (CRC) is the third most frequent cancer usually occurring in elderly persons. However, the molecular characteristics of old-onset CRC remain largely unknown. Here we performed proteomic profiling from 52 CRC tumors and their paired non-cancerous adjacent tissues and delineated the distinct molecular attributes and hallmarks of tumor progression in old-onset CRC patients over 60 years old. Then we screened out candidate proteins highly correlated with age in CRC patients through logistic regression algorithm. Besides comparative proteomic analysis of tumors and NATs revealed a catalog of age-associated proteins, including drug targets, oncogenes, transcription factors and tumor suppressors. Immunohistochemical analysis showed that the CRC patients with high NHP2 expression had lower overall survival rate and the older persons had the worse the prognosis. Cell viability and clone formation experiments revealed that knockdown of NHP2 in HT29 and SW620 cell lines inhibited cell proliferation. Collectively, this study provides a deeper understanding of cancer biology leading to old-onset CRC, and identifies potential biomarkers and therapeutic targets for old-onset CRC patients.