Previous studies have demonstrated that fatigue is a risk factor for depressive symptoms in mothers of young children. The aim of the present study was to investigate whether the five facets of mindfulness moderated the relationship between fatigue and depressive symptoms in mothers of young children. A sample of 723 mothers of children aged 1–5 years completed the Fatigue Assessment Scale, the Centre for Epidemiologic Studies Depression Scale, and the Five Facet Mindfulness Questionnaire-Short Form. Results showed that four out of the five mindfulness facets (non-judging of inner experience, non-reactivity to inner experience, acting with awareness, and describing) weakened the relationship between fatigue and depressive symptoms. Interaction effects were found to be small. Further investigation of the unique roles of the five mindfulness facets as well as other possible protective factors and interventions that may weaken the fatigue-depressive symptom relationship in mothers of young children is warranted.