Colorectal cancer is one of the common malignant tumors with poor prognosis, which is partly due to the lack of an effective biomarker. The purpose of this study is to explore the impact of membrane palmitoylated protein (MPP2) on the prognosis of colorectal cancer patients. We obtained transcriptome data and DNA methylation data of 380 colorectal cancer patients from the Cancer Genome Atlas (TCGA). Then we used a series of bioinformatics analysis methods to reveal the relationship between MPP2 expression, DNA methylation sites, prognosis, immune checkpoint and clinical characteristics of patients. Finally, in vitro experiment and the meta-analysis of thousands of patients further confirmed the impact of MPP2 on the prognosis of colorectal cancer patients and cell migration and proliferation. The expression level of MPP2 is negatively regulated by its DNA methylation sites, which leads to its low expression in colorectal cancer. High expression of MPP2 is an independent prognostic risk factor, which may be a biomarker for colorectal cancer. Moreover, the expression of MPP2 shows a close relationship with immune checkpoint or immune cells infiltration, especially CD4T cells. In addition, meta-analysis involving 1584 patients from four different data further confirmed that MPP2 was a risk factor for colorectal cancer. Finally, knockdown of MPP2 could significantly inhibit the proliferation of SW480 cells via mTOR signaling pathway. This study was the first to suggest that MPP2 may become a promising biomarker, and has an important role in immune checkpoint or immune cell infiltration in colorectal cancer.