Objective To explore the effect of different opioid analgesics on postoperative fatigue syndrome (POFS) after painless gastroscopy. Methods A total of 608 patients who underwent painless gastroscopy were enrolled. According to the random number table method, they were divided into three groups: a control group (group C, n=201), a remifentanil group (group R, n=198) and a butorphanol group (group B, n=209). Group C was intravenously injected with 2.5 mg/kg propofol for anesthesia induction, and maintained by intravenous infusion of propofol at 0.1 mg·kg‒1·min‒1. Group R was intravenously injected with 2.0 mg/kg propofol and 0.5 μg/kg remifentanil for anesthesia induction, and maintained by intravenous infusion of propofol at 0.1 mg·kg‒1·min‒1 and remifentanil at 0.05 μg·kg‒1·min‒1. Group B was intravenously injected with 2.0 mg/kg propofol and 5 μg/kg butorphanol for anesthesia induction, and maintained by intravenous infusion of propofol at 0.1 mg·kg‒1·min‒1. The severity of patient's symptoms, including dizziness, vertigo, headache, drowsiness, and fatigue, was evaluated by the Numerical Rating Scales (NRS). By reference to NRS scores, patient fatigue scores were evaluated by the Christensen Fatigues Scale and patient POFS scores were calculated. The incidence of POFS, POFS score and POFS duration in the three groups were recorded. Changes in sleep duration were recorded in patients with "symptoms still present at night but completely improved after morning rise the next day". Results POFS in 93% of patients was relatively mild (1‒4 points for POFS scores). Group B showed a higher POFS score than group C (P<0.05). The incidence of POFS in group B was higher than those in groups C and R (P<0.05), and the duration of POFS in group B was longer than those in groups C and R (P<0.05). The 15 patients whose "symptoms still existed when they fell asleep at night, and were completely improved when they woke up the next morning" underwent painless gastroscopy and their sleep duration at night was longer than their daily sleep duration (P<0.05). There was no statistical difference in other indexes (P>0.05). Conclusions Different opioid analgesics exert different effects on POFS. Butorphanol and other opioid agonist‑antagonists with long action time may cause more severe POFS. For the prevention of POFS, propofol alone and remifentanil combined with propofol are better anesthetic options.