Objective ·To evaluate the changes in cognitive function in overweight and obese adolescents, and explore the association between cognitive function and fibroblast growth factor 21 (FGF21). Methods ·A total of 175 adolescents from a senior high school in Shanghai were divided into normal weight group (n=50), overweight group (n=50) and obese group (n=75) based on their body mass index (BMI). General information, anthropometric data and laboratory testing indicators of the adolescents were collected and compared. The cognitive function of the three groups of adolescents was assessed by using the accuracy (ACC) and reaction time of Flanker task and n-back task. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum FGF21 level of the three groups of adolescents. Partial correlation analysis and multiple linear regression model were used to evaluate the correlation between cognitive task performance and anthropometric data and laboratory testing indicators. Results ·Compared with the normal weight group, systolic blood pressure, diastolic blood pressure, and the levels of fasting plasma glucose, glycosylated hemoglobin and triacylglycerol in the obese group were higher (all P<0.05). Under congruent or incongruent stimulus conditions in the Flanker task, there was no significant difference in ACC between any two groups; compared with the normal weight and overweight groups, the reaction time of the adolescents in the obese group was prolonged (all P<0.05). In the n-back task, there were no significant differences in ACC between any two groups, while the obese group had longer reaction time in the 1-back and 2-back tasks compared to the normal weight and overweight groups (all P<0.05). Compared with the normal weight group, serum FGF21 levels of the adolescents in the obese group were higher (P=0.000). Partial correlation analysis showed that the reaction time of the adolescents in Flanker and n-back tasks was correlated with their BMI, body fat mass, waist circumference, waist-to-hip ratio and FGF21 level (all P<0.05). Multiple linear regression analysis further confirmed that BMI was associated with prolonged reaction time in cognitive-related behavioral tasks in the adolescents (all P<0.05), and FGF21 level was associated with ACC in the 2-back task (P=0.000) and reaction time in the incongruent stimulus condition (P=0.048). Conclusion ·Overweight and obese adolescents have cognitive impairments, and BMI and serum FGF21 levels are associated with changes in their cognitive function.