Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p < 0.001). Eighty-nine percent of the patients in the severe BDI-II category had poorly controlled asthma (ACQ-5 score ≥ 1.5) compared with 63% in the minimal category (p < 0.001). Conclusion: Increased severity of depressive symptoms was associated with worse respiratory-related quality of life and asthma control in the patients with severe eosinophilic asthma. These findings highlight the need for a multidimensional approach for the management of uncontrolled asthma, including timely identification of depressive symptoms. Additional research is needed to further explore the interactions between the two common conditions.Clinical trials NCT01691521 and NCT01619508, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.