Objective To evaluate the effect of alfentanil or fentanyl combined with propofol on the postoperative cognitive function of elderly patients after painless colonoscopy. Methods A total of 106 elderly patients who underwent painless colonoscopy at Huaibei People's Hospital from March 2019 to October 2020 were enrolled. According to random sequences generated by computer, the patients were divided into two groups: an alfentanil (AP) group and a fentanyl (FP) group. Patients in the AP and FP groups were slowly intravenously injected with 5 μg/kg alfentanil or 0.5 μg/kg fentanyl, followed by closed‑loop target‑controlled infusion of propofol under bispectral index (BIS) monitoring (BIS=55). The infusion of propofol was stopped when the lens moved to the rectum. The following information was collected: general information, the Amsterdam Preoperative Anxiety and Information Scale (APAIS), check‑up time, awaking time, discharge time, propofol dosage and the presence of hypotension, respiratory depression and other adverse reactions. Their Montreal Cognitive Assessment (MoCA) scores were evaluated before examination, before discharge, 1 day after operation, and 3 days after operation. Patient's abdominal pain before discharge was assessed by the Numerical Rating Scale (NRS) scores. The Likert scale was used to assess physician satisfaction and patient satisfaction. Results There was no statistical difference between the two groups in general conditions, APAIS before examination, propofol dosage, examination time, NRS scores, physician and patient satisfactions (P>0.05). The AP group presented remarkably shorter awaking time and discharge time than the FP group (P<0.05). Both groups showed decreases in MoCA scores before discharge, compared with those before examination (P<0.05), where the MoCA score of the AP group was higher than that of the FP group (P<0.05). There was no statistical difference in MoCA score between the two groups at other time points (P>0.05). The incidence of postoperative nausea, vomiting and apnea in the AP group was significantly lower than that in the FP group (P<0.05), and there was no statistical difference in other complications between the two groups (P>0.05). Conclusions Single intravenous injection of alfentanil combined with closed‑loop target controlled infusion of propofol has less effect on the cognitive function of elderly patients after painless colonoscopy, compared with fentanyl and propofol, with good the quality of recovery.