Increasing evidence suggests that circular RNA (circRNA) plays an important role in non‐small cell lung cancer (NSCLC) progression. This study aimed to investigate the role and potential molecular mechanism of circ_0006324 in NSCLC. The expression levels of circ_0006324, miR‐496, miR‐488‐5p, and tripartite motif‐containing 59 (TRIM59) mRNA were determined by quantitative real‐time polymerase chain reaction (PCR). 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide assay, EdU assay, and flow cytometry were carried out to evaluate cell proliferation and apoptosis. The extracellular acidification rate and lactic acid production were examined to assess cell glycolysis. Western blot assay was used to detect protein levels. The target relationship of circ_0006324/miR‐496/TRIM59 axis was validated by RNA pull‐down assay, dual luciferase reporter assay, and radio immunoprecipitation assay. Xenograft tumor assay was performed to reveal the function of circ_0006324 in vivo. Circ_0006324 was upregulated in NSCLC and related to tumor node metastasis stage and distant metastasis. Knockdown of circ_00006324 impeded NSCLC cell proliferation, glycolysis, and promoted cell apoptosis. MiR‐496 was verified as a target of circ_0006324 and circ_00006324 mediated the altering of cell proliferation, apoptosis, and glycolysis of NSCLC cells through targeting miR‐496. TRIM59 was verified as a target of miR‐496, and circ_0006324 positively regulated TRIM59 expression by targeting miR‐496. Overexpression of TRIM59 could reverse the effects of circ_0006324 silencing on the proliferation, apoptosis, and glycolysis of NSCLC cells. Circ_0006324 knockdown impeded NSCLC tumor growth in vivo. Circ_0006324 functioned as a tumor promoter in NSCLC to promote cell proliferation, cell cycle progression, and glycolysis and inhibit cell apoptosis via miR‐496/TRIM59 axis.