The purpose of this study was to determine the extent to which maternal relationship insecurity and severe depressive symptoms moderate home visiting impacts on developmental and behavioral outcomes in 2-year old children. In an experimental trial of the Healthy Families Alaska home visiting program, families (N = 249) were randomly assigned to home visiting (n = 126) or community services as usual (n = 123). Maternal severe depressive symptoms (CES-D ≥ 24) and relationship insecurity were measured using the Center for Epidemiologic Studies Depression Scale and the Attachment Style Questionnaire at baseline. Child cognitive and psychomotor development and behavior problems were measured with the Bayley Scales of Infant Development and the Child Behavior Checklist at follow-up. The results revealed that home visiting significantly impacted three outcomes—child cognitive development, internalizing behavior, and externalizing behavior. Home visiting impacts were limited to subgroups defined by maternal depressive symptoms and relationship insecurity. Home visiting improved cognitive development (B = 6.02, p < .03), and decreased internalizing behavior (B = −3.83, p = .02) and externalizing behavior problems (B = −3.74, p = .03) in children of mothers with either severe depressive symptoms or high levels of discomfort with trust at baseline, but not both. Family engagement in home visiting seems to play a role in mediating these moderating effects. These findings reflect the importance of screening for maternal relationship insecurity and depressive symptoms to distinguish family subgroups likely to benefit from home visiting from those for whom an enhanced service model might be needed.