Abstract: Radiotherapy is a primary treatment for lung cancer, especially for non-small cell lung cancer (NSCLC). Compared with conventional fractionated radiotherapy, hypofractionated radiotherapy (HFRT) is a powerful method in NSCLC treatment because of its convenience and excellent clinical efficacy. Although HFRT has been significantly developed for treating NSCLC, radiation resistance with an unknown molecular mechanism is still observed in tumors. The PI3K/AKT/mTOR signaling pathway significantly affects resistance to conventional fractionated radiotherapy. However, whether this pathway induces radiation resistance to HFRT remains unclear. The underlying molecular mechanisms between HFRT and the PI3K/AKT/mTOR signal pathway may be used as targets in radiation sensitivity or in the modification of radiation resistance in NSCLC patients. New predictive biomarkers can also be expected in the PI3K/AKT/mTOR signaling pathway when the clinical specimen is screened using HFRT.