Radioresistance is an important cause of cancer treatment failure. Circular RNAs (circRNAs) play crucial roles in cancer development, including the radioresistance. This research aimed to determine the function and related mechanism of circ_0086720 in the radioresistance of non-small cell lung cancer (NSCLC). The expression of circ_0086720, miR-375, and Spindlin 1 (SPIN1) was measured using a quantitative real-time polymerase chain reaction (qRT-PCR). Cell survival fraction was analyzed using colony formation assay, and cell apoptosis was monitored by flow cytometry assay. The activities of caspase 3 and caspase 9 were assessed using the corresponding commercial kits. The protein levels of SPIN1 and gamma H2AX were detected by western blot. Bioinformatics analysis was performed to predict the targets of circ_0086720 and miR-375. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA pull-down assay were conducted to validate the interaction between miR-375 and circ_0086720 or SPIN1. The animal model was constructed to ascertain the role of circ_0086720 in vivo. The expression of circ_0086720 and SPIN1 was increased in the radioresistant NSCLC tissues, while miR-375 expression was decreased. The circ_0086720 knockdown sensitized NSCLC cells to the radiation to further inhibit cell survival and induce cell apoptosis. Circ_0086720 targeted miR-375 and suppressed miR-375 expression, and miR-375 bound to SPIN1 to impair SPIN1 expression. miR-375 deficiency or SPIN1 overexpression could attenuate circ_0086720 knockdown-mediated radiosensitivity. The circ_0086720 knockdown also enhanced radiosensitivity to further block tumor growth in vivo. To conclude, circ_0086720 downregulation enhanced the sensitivity of NSCLC to radiation by regulating the miR-375/SPIN1 axis, contributing to the improvement of the radiotherapies in NSCLC.