Aberrant activation of canonical WNT signaling has been implicated in colorectal cancer (CRC) progression. However, the complexity associated with WNT pathway poses challenges to consider it as an effective therapeutic target. Here, we employed a bottom-up approach and delineate the clinical significance of DKC1-driven CRC. We show higher DKC1 expression in ~88% of CRC patients associated with poor recurrence-free survival. Notably, DKC1-positive patients exhibit similarity with CMS2, a class with active WNT signaling. Mechanistically, DKC1 orchestrates cell cycle regulation, maintains genomic integrity, and confers drug resistance. Furthermore, WNT/β-catenin axis modulates DKC1 expression, and WNT inhibitor led to reduced DKC1-mediated oncogenicity. Additionally, mice bearing DKC1-knockdown xenografts show ~81% reduction in tumor burden. Patients’ specimen with high DKC1 levels show accumulation of ceramides, namely C23 and C24. Also, DKC1/SOX2 complex perturbs sphingolipids metabolism via SGPP2 enzyme, leading to elevated ceramides. Overall, we discover the underlying circuitry involved in DKC1-driven CRC, propose ceramides as biomarker, and underscore the utility of WNT-based therapeutics in disease management.