Current evidence indicates that conventional mechanical ventilation often leads to lung inflammatory response and oxidative stress, while lung-protective ventilation (LPV) minimizes the risk of ventilator-associated lung injury (VALI). This study evaluated the effects of LPV on relief of pulmonary injury, inflammatory response, and oxidative stress among patients undergoing craniotomy. Sixty patients undergoing craniotomy received either conventional mechanical (12 mL/kg tidal volume [VT] and 0 cm H2O positive end-expiratory pressure [PEEP]; CV group) or protective lung (6 mL/kg VT and 10 cm H2O PEEP; PV group) ventilation. Hemodynamic variables, lung function indexes, and inflammatory and oxidative stress markers were assessed. The PV group exhibited greater dynamic lung compliance and lower respiratory index than the CV group during surgery (P < 0.05). The PV group exhibited higher plasma interleukin- (IL-) 10 levels and lower plasma malondialdehyde and nitric oxide and bronchoalveolar lavage fluid, IL-6, IL-8, tumor necrosis factor-α, IL-10, malondialdehyde, nitric oxide, and superoxide dismutase levels (P < 0.05) than the CV group. There were no significant differences in hemodynamic variables, blood loss, liquid input, urine output, or duration of mechanical ventilation between the two groups (P > 0.05). Patients receiving LPV during craniotomy exhibited low perioperative inflammatory response, oxidative stress, and VALI.