Background: Non-small cell lung cancer (NSCLC) is the most prevalent cancer in the world. Chemotherapy resistance is a major obstacle to NSCLC therapy. This study explored the role and molecular mechanism of circular RNA 0011292 (circ_0011292) in tumorigenesis and chemoresistance of NSCLC. Methods: The levels of circ_0011292, miR-379-5p, and tripartite motif-containing protein 65 (TRIM65) were measured by quantitative real-time polymerase chain reaction or Western blot assay. Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was monitored by flow cytometry. Cell migration and invasion were detected by transwell assay. The levels of apoptosis-related and epithelial-mesenchymal transition-related proteins were examined by Western blot. The half-inhibition concentration (IC50) of paclitaxel (PTX) was evaluated by CCK-8 assay. Xenograft model was established to analyze the effect of circ_0011292 on PTX resistance of NSCLC in vivo. The interaction among circ_0011292, miR-379-5p, and TRIM65 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results: Circ_0011292 and TRIM65 were upregulated, while miR-379-5p was downregulated in NSCLC tissues and cells. Circ_0011292 knockdown hindered NSCLC progression and enhanced PTX sensitivity of NSCLC. Circ_0011292 silencing reduced PTX resistance in vivo. Besides, miR-379-5p potentiated PTX sensitivity by targeting TRIM65. Also, circ_0011292 increased PTX resistance by sponging miR-379-5p. Conclusion: Circ_0011292 facilitated tumorigenesis and PTX resistance in NSCLC by regulating the miR-379-5p/TRIM65 axis, suggesting that circ_0011292 was a promising therapeutic target for NSCLC chemotherapy.