Background: Awake craniotomy is a well-tolerated procedure for the resection of brain tumors residing within or close to the eloquent cortical areas. Monitored anesthesia care (MAC) is a dominant anesthetic approach for awake craniotomy; however, it is associated with inherent challenges such as desaturation and hypercapnia, which may lead to various complications. The prevention of respiratory insufficiency is important for successful awake craniotomy. As measures to avoid respiratory depression, the use of high-flow nasal cannula (HFNC) can improve patient oxygenation and monitor the oxygen reserve index (ORi) to detect hypoxia earlier. Case: We report two cases of awake craniotomy with MAC using HFNC and ORi. We adjusted the fraction of inspired oxygen of the HFNC according to the ORi level. The patient underwent successful awake craniotomy without a desaturation event or additional airway intervention. Conclusions Combined HFNC and ORi monitoring may provide adequate oxygen reserves in patients undergoing awake craniotomy.