Emerging evidence has manifested the critical effect of abnormally expressed circular RNAs (circRNAs) on the initiation and progression of non-small cell lung cancer (NSCLC). Although circRNA circCCDC66 has been revealed to elicit facilitating impact on cell growth and metastasis in colon cancer, the potential biological function and regulatory mechanism of it in NSCLC still require to be explored. In this study, circCCDC66 in NSCLC cells was highly expressed. Downregulation of circCCDC66 impaired cell proliferation, migration and invasion whereas boosted cell apoptosis in NSCLC. Data from molecular mechanism assays testified that circCCDC66 bound with miR-33a-5p in NSCLC cells. And miR-33a-5p inhibition could rescue the suppressive effect of circCCDC66 knockdown on NSCLC progression. In addition, karyopherin subunit alpha 4 (KPNA4) in NSCLC cells was proofed to be directly targeted by miR-33a-5p. Moreover, through rescued-function assays, we observed that upregulating KPNA4 expression could countervail the restraining function of silenced circCCDC66 on NSCLC progression. Furthermore, signal transducer and activator of transcription 3 (STAT3) was validated to activate CCDC66 transcription and thereby promote circCCDC66 expression in NSCLC cells. Briefly, STAT3-induced circCCDC66 upregulation accelerates NSCLC progression via miR-33a-5p/KPNA4 axis, suggesting circCCDC66 as a promising biomarker in NSCLC treatment.