Cognitive impairments contribute significantly to psychosocial dysfunction in major depressive disorder (MDD), yet mechanistically selective treatments targeted to these impairments are lacking. We evaluated guanfacine immediate release (GIR), an alpha 2A receptor agonist, as a novel treatment for selectively improving cognitive control circuit function and behavioral performance in a subtype of depression, the cognitive biotype. Seventeen MDD participants of this biotype completed 6-8 weeks of GIR treatment (target dose: 2mg/night), meeting our per protocol criteria. GIR significantly increased activation and connectivity within the cognitive control circuit. The clinical response rate was 76.5% (defined by ≥ 50% improvement on the 17-item Hamilton Rating Scale for Depression (HRSD-17), exceeding conventional antidepressant rates, and 64.7% achieved remission (HRSD-17 score of ≤ 7). GIR significantly improved cognitive control performance, quality of life, and global life satisfaction. This study is the first to demonstrate both efficacy and target engagement of GIR as a mechanistically selective treatment specifically for the cognitive biotype of depression.