This study examined the relationship between loneliness, health, and mortality using a U.S. nationally representative sample of 2101 adults aged 50 years and over from the 2002 to 2008 waves of the Health and Retirement Study. We estimated the effect of loneliness at one point on mortality over the subsequent six years, and investigated social relationships, health behaviors, and health outcomes as potential mechanisms through which loneliness affects mortality risk among older Americans. We operationalized health outcomes as depressive symptoms, self-rated health, and functional limitations, and we conceptualized the relationships between loneliness and each health outcome as reciprocal and dynamic. We found that feelings of loneliness were associated with increased mortality risk over a 6-year period, and that this effect was not explained by social relationships or health behaviors but was modestly explained by health outcomes. In cross-lagged panel models that tested the reciprocal prospective effects of loneliness and health, loneliness both affected and was affected by depressive symptoms and functional limitations over time, and had marginal effects on later self-rated health. These population-based data contribute to a growing literature indicating that loneliness is a risk factor for morbidity and mortality and point to potential mechanisms through which this process works.