Objective To explore the accuracy of pupillary index in predicting pain after awakening in patients undergoing general anesthesia. Methods A total of 161 patients, aged 18 to 65 years, who were scheduled to undergo orthopedic surgery under general anesthesia from February 2021 to February 2022 were enrolled. According to the Verbal Rating Scale (VRS) score at the time of when patients expressing pain clearly after surgery (T8), the patients were divided into two groups: a painless group (VRS=0 score, n=91) and a pain group (VRS≥1 score, n=70). The patients were subjected to routine anesthesia induction. Both groups were compared for pupillary diameter (PD, represented as PD1‒PD8) and pupillary light reflex velocity (PLRV) when the patients entered the operating room (T1), before incision (T2), 10 s after incision (T3), 30 s after incision (T4), 1 h after incision (T5), at the end of the operation (T6), at extubation (T7) and T8. Data with statistical differences were included in a logistic regression to analyze the risk factors for pain after awakening. Spearman's correlation was used to analyze the relationships among PD, PLRV, and VRS scores. The accuracy of PD and PLRV in predicting pain after awakening was analyzed by the receiver operating characteristic curve. Results PD3‒PD7 in the pain group were higher than those in the painless group (P<0.05). Compared with PD1, PD2‒PD8 decreased in two groups (P<0.05). Compared with PD2, PD3‒PD8 increased in two groups (P<0.05). There was no statistical difference in PLRV between the two groups at T1‒T8 (P>0.05). Compared with those at T1, PLRV in both groups decreased from T2‒T8 (P<0.05). Compared with those at T2, PLRV in both groups increased at T7‒T8 (P<0.05). Logistic multivariate analysis showed that PD4 (odds ratio (OR) 3.171 [95% confidence interval (CI) 0.547, 5.663), PD5 [OR 6.528 (95%CI 2.135, 8.168)], PD6 [OR 64.29 (95%CI 14.547, 289.689)] and PD7 [OR 70.517 (95%CI 27.143, 183.495)] were the risk factors for pain after awakening (P<0.05). PD4‒PD7 was correlated with VRS score after awakening (r=0.188, 0.217, 0.684, and 0.721, P<0.05). The receiver operating characteristic curve showed that the cut‑off values of PD6 and PD7 for predicting pain after awakening were 2.05 mm and 2.25 mm, where the sensitivity was 0.857 and 0.757, respectively, the specificity was 0.802 and 0.923 respectively, and the area under the curve was 0.903 and 0.927 respectively. Conclusion PD is a valuable index to predict pain after awakening from general anesthesia.