Colon cancer is a common malignant tumor. However, its pathogenesis still needs further study. In this study, we explored the role of nucleosome assembly protein 1-like 1 (NAP1L1) in colon cancer and its underlying mechanism. Based on analysis of The Cancer Genome Atlas data, we found that NAP1L1 is augmented in colorectal cancer, and the elevated NAP1L1 expression is associated with a poor prognosis in patients with colon cancer. Immunohistochemistry staining results showed that upregulated NAP1L1 protein level is an unfavorable factor that stimulates colon cancer progression. To further investigate the role of NAP1L1 in colon cancer, we established a colon cancer cell line with NAP1L1 knockdown, and found that repressing NAP1L1 expression in colon cancer cells markedly reduces cell proliferation in vivo and in vitro by MTT assay, colony formation, EdU incorporation, and subcutaneous tumorigenesis in nude mice. Furthermore, we found that NAP1L1 binds to HDGF, recruits DDX5, and induces β-catenin/CCND1 signaling, which promotes colon cancer cell proliferation. Finally, transfection with HDGF or DDX5 restores cell growth in NAP1L1-knockdown colon cancer cells by upregulating DDX5/β-catenin/CCND1 signaling. Our study demonstrates that NAP1L1 functions as a potential oncogene that promotes colon cancer tumorigenesis by binding to HDGF, which stimulates DDX5/β-catenin/CCND1 signaling.