The one‑lung ventilation (OLV) technique is vital in thoracic surgery. However, it can result in severe lung injury, which is difficult to manage. The main solution at present is the use of ventilation strategies, including continuous positive oxygen pressure, low tidal volume and high frequency ventilation, and the administering of drugs, including phenylephrine, dexmedetomidine and morphine. However, the protective effect of these methods on the lungs is not sufficient to improve the prognosis of patients. Therefore, how to develop a novel protective drug remains an open question. Nicorandil, a mitochondrial (mito)KATP‑specific opener, serves an important role in cardioprotection, although its effect on lung injury remains unclear. The present study examined the protective role of nicorandil against collapse‑induced lung injury in rabbits undergoing OLV. Changes in arterial oxygen saturation (SaO2), arterial partial pressure for oxygen (PaO2), wet/dry weight ratio, and the microstructure of tissues and cells were observed. Enzyme‑linked immunosorbent assays were used to determine the concentrations of malondialdehyde (MDA) and tumor necrosis factor (TNF)‑α, and the activity of superoxide dismutase (SOD) in rabbits treated with nicorandil. Terminal deoxynucleotidyl transferase transfer‑mediated dUTP nick end‑labeling was used to detect apoptosis and western blotting was used to analyze the relative proteins involved in apoptosis. Western blotting and reverse transcription‑quantitative polymerase chain reaction analysis were used to examine the expression of hypoxia inducible factor 1α (HIF‑1α), phosphatidylinositol‑3‑kinase (PI3K), protein kinase B (Akt) and nuclear factor (NF)‑κB in the lungs of rabbits treated with nicorandil. The SaO2 and PaO2 in the high‑dose group were significantly higher than those in the control group in the process of OLV. The wet/dry weight ratio, and the concentrations of MDA and TNF‑α in the collapsed lung of the high‑dose group were significantly lower than those in the control group. The activity of SOD in the high‑dose group was significantly higher than that in the control group. The lung had improved microstructure and less apoptosis, which was determined by the Bax/Bcl2 ratio in the high‑dose group. The expression levels of PI3K, phosphorylated Akt and HIF‑1α were upregulated, whereas the expression of NF‑κB was downregulated. In conclusion, nicorandil had a protective effect via inhibiting apoptosis in non‑ventilated lung collapsed and re‑expansion during OLV in the rabbit. It acted on mitoKATP through the PI3K/Akt signaling pathway.