The roles of aberrantly regulated autophagy in human malignancy and the mechanisms that initiate and sustain the repression of autophagy in carcinogenesis are less well defined. Activation of the oncogene UBE2C and repression of autophagy are concurrently underlying the initiation, progression, and metastasis of lung cancer and exploration of essential association of UBE2C with autophagy will confer more options in searching novel molecular therapeutic targets in lung cancer. Here we report that aberrant activation of UBE2C in lung tumors from patients associates with adverse prognosis and enhances cell proliferation, clonogenicity, and invasive growth of NSCLC. UBE2C selectively represses autophagy in NSCLC and disruption of UBE2C-mediated autophagy repression attenuates cell proliferation, clonogenicity, and invasive growth of NSCLC. Autophagy repression is essentially involved in UBE2C-induced cell proliferation, clonogenicity, and invasive growth of NSCLC. Interference of UBE2C-autophagy repression axis by Norcantharidin arrests NSCLC progression. UBE2C is repressed post-transcriptionally via tumor suppressor miR-381 and epitranscriptionally stabilized with maintenance of lower m6A level within its mature RNAs due to the upregulation of m6A demethylase ALKBH5 in NSCLC. Collectively, our results indicated that deregulated UBE2C-autophagy repression axis drives NSCLC progression which renders varieties of potential molecular targets in cancer therapy of NSCLC.