Interpersonal strain is linked with depressive symptoms in middle-aged adults. Self-compassion is an emerging resilience construct that may be advantageous in navigating relationship strain by helping individuals respond to emotions in a kind and nonjudgmental way. Although theory and empirical evidence suggests that self-compassion is protective against the impact of stress on mental health outcomes, many studies have not investigated how self-compassion operates in the context of relationship strain. In addition, few studies have examined psychological or physiological mechanisms by which self-compassion protects against mental health outcomes, depression in particular. Thus, this study examined 1) the extent to which trait self-compassion buffers the relation between family strain and depressive symptoms, and 2) whether these buffering effects are mediated by hope and inflammatory processes (IL-6) in a sample of 762 middle-aged, community-dwelling adults. Results from structural equation models indicated that family strain was unrelated to depressive symptoms and the relation was not moderated by self-compassion. Hope, but not IL-6, mediated the relation between family strain and depressive symptoms and the indirect effect was not conditional on levels of self-compassion. Taken together, the findings suggest that family strain may lead individuals to experience less hope and subsequent increases in depressive symptoms, and further, that a self-compassionate attitude does not affect this relation. Implications for future self-compassion interventions are discussed.