As a selective histone deacetylase (HDAC) inhibitor developed in China, chidamide has been applied for the treatment of refractory peripheral T-cell lymphoma (PTCL) and multiple solid tumors, including lung cancer. However, the underlying mechanisms are not well elucidated. In our present study, we found that chidamide and radiation acted synergistically to suppress cell and xenograft growth of lung squamous cell carcinoma cells by inducing cell apoptosis. Moreover, chidamide alone or a combination of chidamide and radiation treatment inhibited cancer cell stemness. miRNA microarray analysis demonstrated that miR-375 was the highest upregulated microRNA (miRNA) in NCI-2170 and NCI-H226 cells treated with chidamide alone or treated with chidamide plus radiation, compared with normal control. Inhibition of miR-375 attenuated the promoting effect of chidamide alone and chidamide plus radiation-induced NCI-2170 and NCI-H226 cell apoptosis and reverted the suppression of cancer stemness caused by chidamide alone or chidamide plus radiation treatment. Moreover, EIF4G3, a scaffold protein in the translation initiation complex, was found to be a direct target of miR-375 based on the luciferase reporter assay and western blot analysis. Interestingly, both chidamide alone and chidamide plus radiation treatments suppressed the mRNA and protein expression of EIF4G3. Silence of EIF4G3 also induced cell apoptosis and suppressed tumor growth in NCI-2170 and NCI-H226 cells. These data suggest that chidamide shows a synergistic effect with radiation therapy on lung squamous cell carcinomas by modulating the miR-375-EIF4G3 axis, which may afford an effective strategy to overcome the drug resistance of chidamide in clinical cancer therapy.