Background <p>Depression with cognitive impairment impairs the social and learning abilities of adolescents, causing great trouble in their lives and families.</p> Aim <p>To investigate the effect of miR-17-92 rs9588884 gene polymorphism on adolescents with depression with cognitive impairment.</p> Methods <p>155 adolescents with depression without cognitive impairment and 165 adolescents with depression with cognitive impairment were included in this study. The distribution of the miR-17-92 rs9588884 genotype was detected by the TaqMan probe method. miR-17-92 expression in serum was detected by RT-qPCR. Correlation between miR-17-92 expression and HAMD Score, MoCA Score, and MMSE Score was analyzed by Pearson correlation coefficient. Logistic regression was used to analyzed clinical factors and the risk factors in adolescents with depression with cognitive impairment.</p> Results <p>The distribution of the miR-17-92 rs9588884 CC genotype and C gene frequency is relatively high, and the CC genotype is the pathogenic genotype for adolescents with depression and cognitive impairment. Patients with the CC genotype had higher levels of depression and more severe cognitive impairment. The expression of miR-17-92 in adolescents with depression with cognitive impairment was lower than those of adolescents with depression without cognitive impairment. miR-17-92 expression was lower in CC genotype than CG + GG genotype in adolescents with depression with cognitive impairment. The HAMD Score, MoCA Score, MMSE Score, and miR-17-92 rs9588884 CC genotype were risk factors for depressive cognitive impairment.</p> Conclusion <p>The miR-17-92 rs9588884 CC genotype is pathogenic, and miR-17-92 expression was reduced in adolescents with depression with cognitive impairment.</p>