Although the combination of etoposide (VP16) and cisplatin (DDP) is widely used as a first-line treatment for advanced-stage small-cell lung cancer (SCLC), chemoresistance limits its clinical use. Abnormalities of autophagy are associated with tumor chemoresistance. The present study found that miR-24-3p, a recently discovered microRNA, is significantly downregulated in VP16-DDP-resistant SCLC cells (H446/EP) compared with VP16-DDP-sensitive parent cells (H446). Forced expression of miR-24-3p sensitized H446/EP cells to VP16-DDP treatment because of a blockade of autophagic activity. We further found that downregulated miR-24-3p enhanced autophagy activation as it directly targets and inhibits autophagy-associated gene 4A (ATG4A). Overexpression of miR-24-3p into H446/EP cells led to reduction of the ATG4A protein level, allowing SCLC cells to resensitize to VP16-DDP. We conclude that miR-24-3p regulates autophagy by targeting ATG4A. Inhibition of autophagy by increasing miR-24-3p could be the basis of a strategy to prevent and treat SCLC with combination chemotherapy, particularly in chemoresistant disease.