Up-regulation of Uridine-cytidine kinase 2 (UCK2), a rate-limiting enzyme of the pyrimidine salvage pathway, has been suggested in HCC, but the detailed molecular mechanisms and therapic role of UCK2 remain elusive. Bioinformatic analyses revealed that UCK2 might be a key up-regulated metabolic gene in HCCs. The expressional pattern and prognostic value of UCK2 were further examined in a large number of clinical samples. Functional assays based on site-directed mutagenesis showed that UCK2 promoted cell proliferation in a metabolic manner, but non-catalytically facilitates HCC metastasis. Mechanistically, in response to EGF, UCK2 interacted with EGFR to block EGF-induced EGFR ubiquitination and degradation, which resulted in elevated EGFR-AKT pathway activation and metastasis enhancement in HCCs. Concurrent pharmacological targeting on UCK2 and EGFR showed synergistic effects on HCC treatment. This study disclosed the non-metabolic role of UCK2 and suggested the therapeutic potential of concurrent blocking the metabolic and non-metabolic roles of UCK2 in HCC treatment.