A lack of meaningful social connections, frequently measured through loneliness and social isolation, has been linked to increased risk for a variety of physiological health problems. One potential mechanism through which social disconnection may contribute to health is the hypothalamic-pituitary-adrenal (HPA) axis and its end product, cortisol. This chapter reviews evidence linking loneliness and social isolation to altered cortisol reactivity, diurnal cortisol rhythms, and accumulated cortisol in hair and urine. As HPA axis functioning changes across the lifespan, this chapter also attends to differences in findings between age groups. The current literature suggests that social isolation is frequently linked to alterations in cortisol secretion among middle-aged and older adults, while loneliness is more tightly associated with disruptions in daily cortisol among youth. The chapter underscores the need for longitudinal, multi-method research to disentangle the contributions of social disconnection to HPA axis function and physical health across the lifespan.