Neurochondrin (NCDN) has been recently identified as overexpressed in liver metastatic colorectal cancer (CRC) cells compared to poorly metastatic isogenic counterparts. While its cellular function and role in cancer and CRC remain unknown, patient survival data indicate that elevated NCDN levels are associated with poor patients’ prognosis. After validating these observations in an independent patient cohort, we sought to investigate the role of NCDN in CRC progression using an isogenic CRC cell model comprising poorly metastatic KM12C cells and liver-metastatic KM12SM cells. Stable silencing of NCDN expression in both cell lines resulted in a marked reduction in their tumorigenic and metastatic properties in vitro. Furthermore, in vivo assays using nude mice demonstrated that NCDN is essential for tumor initiation, growth, and liver metastasis of CRC cells. Proteomic profiling of NCDN-silenced cells uncovered a set of dysregulated proteins associated with cell adhesion, invasion, cell death and differentiation, and mitochondrial function, showing that the NCDN-PODXL-Ezrin axis constitutes a critical mediator of CRC liver metastasis. Our findings position NCDN and their associated dysregulated proteins as drivers of metastatic progression in CRC and promising targets for further investigation.