Depression adversely predicts prognosis in individuals with symptomatic heart failure. In some clinical populations, spiritual wellness is considered to be a protective factor against depressive symptoms. This study examined associations among depressive symptoms, spiritual wellbeing, sleep, fatigue, functional capacity, and inflammatory biomarkers in 132 men and women with asymptomatic stage B heart failure (age 66.5 years ± 10.5). Approximately 32 % of the patients scored ≥10 on the Beck Depression Inventory, indicating potentially clinically relevant depressive symptoms. Multiple regression analysis predicting fewer depressive symptoms included the following significant variables: a lower inflammatory score comprised of disease-relevant biomarkers (p < 0.02), less fatigue (p < 0.001), better sleep (p < 0.04), and more spiritual wellbeing (p < 0.01) (overall model F = 26.6, p < 0.001, adjusted R square = 0.629). Further analyses indicated that the meaning (p < 0.01) and peace (p < 0.01) subscales, but not the faith (p = 0.332) subscale, of spiritual wellbeing were independently associated with fewer depressive symptoms. Interventions aimed at increasing spiritual wellbeing in patients lives, and specifically meaning and peace, may be a potential treatment target for depressive symptoms asymptomatic heart failure.