Objective To investigate the effects of different ventilation strategies on regional cerebral oxygen saturation (rScO2), malondialdehyde (MDA), superoxide dismutase (SOD) levels and postoperative delirium (POD) incidence in elderly patients with thoracoscopic radical resection of lung cancer. Methods A total of 68 cases elderly patients admitted to University of Chinese Academy of Sciences Shenzhen Hospital from January 2018 to May 2020 who underwent thoracoscopic radical resection of lung cancer were divided into the control group [34 cases, receiving lung protective ventilation strategy (LPVS)] and the observation group (34 cases, receiving rScO2-oriented LPVS) according to the random number table method, both groups were observed for 7 days after operation. Perioperative indexes, and the rScO2, serum MDA and SOD levels before anesthesia induction (T0), 5 min after total-lung ventilation (TLV) (T1), end of one-lung ventilation (OLV) and before lung recruitment (T2), before tracheal extubation in TLV (T3), intraoperative dosage of anesthetic drugs, postoperative complications, and the POD incidence 3 and 5 days after operation of patients in the two groups were compared. Results The fluid volume in the observation group of patients significantly increased and the stay time in the anesthesia recovery room significantly shortened compared with the control group; compared with T0, the rScO2 level of patients in the two groups showed a trend of first decreasing and then increasing from T1 to T3, and the level of rScO2 in the observation group was significantly higher than that in the control group at T2; compared with T0, the serum MDA level from T1 to T3 showed a gradually increasing trend, and the level of serum MDA in the observation significantly decreased compared with the control group at T3, the level of serum SOD decreased gradually, and the level of serum SOD in the observation significantly increased compared with the control group at T3; the incidence of atelectasis and hypoxemia in the observation group of patients significantly lower than those in the control group; compared with 3 d after operation, the incidence of POD in the control group significantly decreased 5 d after operation, and the incidenceof POD in the observation group was significantly lower than that in the control group 3 d after operation (all P<0.05); the incidence of POD in the observation group at 5 d after operation was lower than that at 3 d after operation and in the control group, but the difference was not statistically significant(all P>0.05). Conclusion rScO2-oriented LPVS can effectively maintain the level of rScO2 during perioperative period in elderly patients undergoing thoracoscopic radical resection of lung cancer, alleviate oxidative stress response, reduce the occurrence of postoperative POD and the incidence of complications.