Objective To observe the application of Nalbuphine combined with Propofol anesthesia in elderly patients undergoing painless gastroscopy and its influence on cognitive function, and explore the appropriate dosage selection of Nalbuphine combined with Propofol in treatment of painless gastroscopy of elder patients.Methods 156 patients underwent painless gastroscopy from February 2018 to January 2020 were enrolled in this study. Which was divided into Low dose Nalbuphine+Propofol group (LNP), middle dose Nalbuphine+Propofol group (MNP), high dose Nalbuphine+Propofol group (HNP). The additional dose of Propofol, operation time, recovery time, mini mental status examination (MMSE) scores, adverse rate and anesthesia effect in the three groups was compared. TNF-α and IL-6 was detected by ELISA.Results There was no significant difference in operation time among the three groups (P > 0.05). The additional dose of Propofol in MNP and HNP group was lower than that in LNP group, and recovery time in MNP and HNP group was shorter than that in LNP group (P < 0.01). There was no significant difference of additional dose of Propofol and recovery time between MNP and HNP group (P > 0.05). The anesthesia effect in MNP and HNP group was 94.2% and 96.2%, which was higher than that of 80.8% in LNP group (P < 0.05). There was no significant difference of anesthesia effect between MNP and HNP group (P > 0.05). There was no significant difference in TNF-α and IL-6 expression among the three groups before examination (P > 0.05). After waking up for 30 minutes, the TNF-α and IL-6 expression in MNP and HNP group was lower than that in LNP group (P < 0.01). There was no significant difference of TNF-α and IL-6 expression between MNP and HNP group (P > 0.05). There was no significant difference in MMSE scores among the three groups before anesthesia (P > 0.05). After 24 h of anesthesia, the MMSE scores in MNP and HNP group was higher than that in LNP group (P < 0.01). There was no significant difference of MMSE scores between MNP and HNP group (P > 0.05). The incidence of vertigo in LNP group and MNP group was significantly lower than that in HNP group (P < 0.05). There was no significant difference of vertigo incidence between LNP and MNP group (P > 0.05).Conclusion In elder patients with painless gastroscopy, moderate dose of Nalbuphine combined with Propofol can obtain significant anesthetic effect, and have little influence on cognitive function, which reduced inflammatory stress response and adverse reactions.