This dataset was generated based on the hypothesis that FAM64A promotes colorectal cancer aggressiveness by reprogramming the cellular proteome. Quantitative proteomic analysis was performed by LC-MS/MS on three groups of SW480 cells: the FAM64A overexpression group, the FAM64A knockdown group, and the control group. The data showed that FAM64A not only significantly changed the abundance of proteins associated with cell proliferation and invasion but also drove the reprogramming of proteins related to lipid and carbohydrate metabolism. Therefore, these findings provide a molecular mechanism to explain how FAM64A promotes cancer progression. This data is of great value as it can be used to further mine biomarkers, study tumor metabolism, or construct signaling networks.