Transcription factor forkhead box D1 (FOXD1), a member of forkhead box family, has been recognized as a caner-related gene. Aberrant expression of FOXD1 is observed in glioma, lung cancer and breast cancer. However, the clinical significance of FOXD1 and its role in colorectal cancer (CRC) are unknown. Here, we found that FOXD1 displayed a higher expression in CRC tissues compared to tumor-adjacent tissues. Upregulation of FOXD1 was further confirmed in CRC tissues compared to normal tissues based on data from three GSE cohorts. Our clinical data indicated that high FOXD1 level was associated with tumor size (≥5 cm) and TNM tumor stage (III + IV). Moreover, both our data and TCGA data found that high expression of FOXD1 predicted poor prognosis of CRC patients. Next, we revealed that FOXD1 knockdown suppressed proliferation, cell cycle progression and induced apoptosis of SW480 cells in vitro. In accordance, FOXD1 overexpression promoted proliferation and reduced apoptosis of HT29 cells. Interestingly, polo-like kinase 2 (Plk2) expression was elevated and it positively correlated with FOXD1 expression in CRC tissues. FOXD1 promoted the expression of Plk2 mRNA and protein in CRC cells. Notably, Plk2 restoration abolished the effect of FOXD1 knockdown on proliferation and apoptosis of SW480 cells. Plk2 knockdown resulted in decreased proliferation and increased apoptosis of FOXD1-overexpressing HT29 cells. Altogether, we demonstrate for the first time that FOXD1 functions as an oncoprotein and a potential prognostic biomarker in CRC.