Circular RNA (circRNA) is currently considered to be a key regulatory molecule in cancer biology. In the present study, we aimed to explore the functional and clinical roles of circ-SLC7A6 (a circRNA derived from SLC7A6 gene) in non-small cell lung cancer (NSCLC). Circ-SLC7A6 was significantly downregulated in NSCLC tissues in comparison to para-carcinoma tissues. Low circ-SLC7A6 was closely associated with larger tumor size, lymph node metastasis, advanced clinical stage and adverse outcome. Exogenous expression of circ-SLC7A6 evidently inhibited the proliferation and invasion of NSCLC cells. Further investigations revealed that miR-21 was the direct functional target of circ-SLC7A6, in which circ-SLC7A6 abundantly sponged miR-21 and elevated a cohort of tumor suppressors, thus inhibiting NSCLC progression. Interestingly, QKI, elevated by circ-SLC7A6, could directly bind to the introns flanking circ-SLC7A6 to facilitate circ-SLC7A6 production. Importantly, xenograft tumor experiments showed that reintroduction of circ-SLC7A6 retarded tumor growth as well as decreased lung metastatic nodules. Overall, our study demonstrates that circ-SLC7A6 is a novel tumor suppressor in NSCLC, targeting circ-SLC7A6/miR-21 axis may be a promising treatment for NSCLC patients.