Purpose: To explore the effects of depression on cognitive flexibility in adolescents, and to provide evidence for the prevention and treatment of mental illness and the reduction of the effects of depression on cognitive flexibility in adolescents. Methods: PHQ-9 depression scale was used to measure the depression degree of 80 adolescents in the depression group and the healthy group, and the subjects participated in Stroop test to record their correct rate and response time. Results: (1) The degree of depression in the depression group was statistically significant (t=2.7, p < 0.01); (2) In Stroop test, the correct rate of the depressed group was lower than that of the healthy group (t=-3.09, p < 0.01), and the response time was higher than that of the healthy group (t=4.79, p < 0.01), which showed a significant difference, indicating that the patients with depression had cognitive flexibility impairment. (3) The degree of depression was negatively correlated with Stroop test accuracy (r=-0.388), and positively correlated with reaction time (r=0.487), and the correlation was significant. Conclusion: Depression has a negative effect on adolescents’ cognitive flexibility. Physical therapy, psychological therapy and physiological therapy can be used to reduce the damage of depression on adolescents’ cognitive function, so as to promote the prevention and treatment of adolescent depression.