Background This study intended to investigate the potential mechanism of microRNA‐200c‐3p (miR‐200c‐3p) and miR‐485‐5p in mediating the cisplatin (DDP) resistance in non–small cell lung cancer (NSCLC). Methods Quantitative real‐time polymerase chain reaction (qRT‐PCR) was applied to measure the expression of miR‐200c‐3p, miR‐485‐5p, and ribonucleotide reductase regulatory subunit M2 (RRM2) messenger RNA (mRNA). 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was used to analyze the DDP resistance and the proliferation of NSCLC cells. Colony formation assay was used to assess cell proliferation. Transwell assays were used to evaluate cell migration and invasion. The target relationship between RRM2 and miR‐200c‐3p or miR‐485‐5p was verified using dual‐luciferase reporter assay. The protein level of RRM2 was measured using Western blot assay. Animal experiments were conducted to analyze the roles of miR‐200c‐3p and miR‐485‐5p in the DDP resistance of xenograft tumors in vivo. Results MiR‐200c‐3p and miR‐485‐5p were both downregulated in DDP‐resistant NSCLC tissues and cell lines. Overexpressing miR‐200c‐3p or miR‐485‐5p suppressed the DDP resistance and malignant behaviors of NSCLC cells. MiR‐200c‐3p played a synergistic role with miR‐485‐5p in regulating the chemo‐resistance and biological behaviors NSCLC cells. RRM2 was confirmed as a target of miR‐200c‐3p and miR‐485‐5p. RRM2 silencing restrained the DDP resistance and progression of NSCLC. RRM2 overexpression partly reversed miR‐200c‐3p or miR‐485‐5p‐induced influences in NSCLC cells. The overexpression of miR‐200c‐3p or miR‐485‐5p aggravated DDP‐mediated suppressive effect on tumor growth in vivo. Conclusion MiR‐200c‐3p or miR‐485‐5p enhanced the DDP sensitivity and suppressed the malignant behaviors of NSCLC cells partly through targeting RRM2. MiR‐200c‐3p and miR‐485‐5p were poorly expressed in DDP‐resistant NSCLC. RRM2 acted as a target of both of them, and miR‐200c‐3p and miR‐485‐5p sequestered RRM2 expression to regulate the proliferation, migration, invasion, and apoptosis of DDP‐resistant NSCLC cells via regulating the PI3K/AKT signaling pathway.