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MicroRNAs (miRNAs/miRs) are known to play a key role in tumorigenesis and usually serve as therapeutic targets in cancer treatment. In the present study, the inhibitory effects and the targeting miRNAs of withaferin A (WA) were investigated in human lung cancer cells. Different lung cancer cell lines were administrated with different concentrations of WA for different time interval followed by western blot or reverse transcription-quantitative PCR analyses to determine the underlying signaling pathway. The results demonstrated that WA decreased the viability of lung cancer cells in a caspase-dependent manner. Further investigations indicated that treatment with WA induced the expression of proapoptotic molecules, p53 and Bax, and decreased Bcl-2 expression in A549 cells. Notably, the results demonstrated that WA also decreased the motility of lung cancer cells in a dose-dependent manner, at a relatively lower concentration. Western blot analysis revealed increased E-cadherin and decreased vimentin expression levels in lung cancer cells treated with WA. In addition, two oncomiRs, including miR-10b and miR-27a, which regulate the expression of E-cadherin and Bax, respectively, were downregulated in the presence of WA. The ectopic expression of miR-10b mimics was able to recover the WA-decreased motility of lung cancer cells, which was accompanied by a reduction in E-cadherin expression. Conversely, the ectopic expression of miR-27a mimics decreased the expression of Bax and recovered the viability of lung cancer cells attenuated by WA. In addition, the ectopic expression of p53-wild type decreased the expression levels of both miR-10b and miR-27a, whereas p53 knockdown induced their expression. Transient knockdown of p53 decreased the inhibitory effects of WA in the motility and viability of lung cancer cells, suggesting an association between WA-p53-miR-10b/27a and motility/viability. Further investigations demonstrated that p53 knockdown in lung cancer stable cell lines exhibited higher levels of both miR-10b and miR-27a, and higher motility and viability following treatment with WA. However, suppression of miR-10b and miR-27a effectively decreased motility and viability, respectively, following treatment with WA. Taken together, the results of the present study suggest that WA inhibits the functionality of lung cancer cells by decreasing the expression levels of both miR-10b and miR-27a in a p53-dependent manner.