Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are prevalent in patients with asthma. These disorders may increase asthma severity and decrease asthma control. No studies have evaluated the impact of achieving antidepressant target dose optimization compared with not achieving antidepressant target doses on asthma control in uninsured and underinsured patients. To evaluate the impact of achieving antidepressant target dose optimization in uninsured and underinsured adult asthma patients with GAD and/or MDD on the risk of severe asthma exacerbations and number of asthma-related outcomes. We conducted a retrospective cohort study of uninsured and underinsured adult asthma patients with GAD and/or MDD who have been initiated on a single antidepressant and maintained on a stable dose for 8 weeks (index date). Eligible patients were followed for 12-24 months after the index date and separated into those who achieved a target dose (target group) and those who did not (control group). Poisson regression was used to compare the risk of severe exacerbations, and analysis of covariance was used to compare the number of severe exacerbations and other asthma-related outcomes between the target and control groups during the 1- and 2-year post-index periods. A total of 61 patients (24 in the target group and 37 in the control group) met inclusion criteria. The target group had a reduced risk of severe asthma exacerbations compared with the control group during the 1-year post-index (adjusted risk reduction [RR] 0.46, 95% confidence interval [CI] 0.26-0.82) and 2-year post-index (adjusted RR 0.5, 95% CI 0.3-0.82) periods. The target group also experienced a lower number of severe asthma exacerbations and other asthma-related outcomes during the 1- and 2-year post-index periods compared with the control group after adjusting for confounders. Among uninsured and underinsured asthma patients with GAD and/or MDD who were initiated on a single antidepressant, those who were titrated to achieve target doses had a reduced risk of severe asthma exacerbations and a lower number of asthma-related outcomes than those who were not optimized to achieve target doses. © 2020 Pharmacotherapy Publications, Inc.