Asthma morbidity and mortality are disproportionately higher among African American children. Medication adherence is essential for reducing adverse asthma outcomes in this population. Depressive symptoms, prevalent among mothers of children with asthma, have been linked to medication nonadherence. This longitudinal, multilevel analysis used data from a randomized clinical trial evaluating the efficacy of an environmental control educational intervention to evaluate the relationship between caregiver depressive symptoms (Center for Epidemiologic Studies Depression Scale) and caregiver-reported medication adherence (Medication Adherence Report Scale) in urban African American children with uncontrolled asthma (N = 208) at baseline, in six months, and in 12 months. Nearly a third (31.7%) of caregivers (97% female) had clinically significant depressive symptoms at baseline. A random intercept model showed that the within-caregiver effect of depression predicted lower medication adherence (β = –.079, p = .002) as did time (β = –.413, p < .001); the between-caregiver effect of depression did not (β = –.007, p = .77). Changes in a caregiver’s baseline level of depressive symptoms appear to have a stronger influence on medication adherence than mean level of depressive symptoms. Policy, practice, and further research should address maternal mental health as a key element in the life course of African American children with asthma.