Loneliness is defined as the subjective feeling that one's social needs are not satisfied by both quantity and quality of one's social relationships. Loneliness has been linked to a broad range of adverse physical and mental health consequences. There is an interest in identifying the neural and molecular processes by which loneliness adversely affects health. Prior imaging studies reported divergent networks involved in cognitive, emotional, and social processes associated with loneliness. Although loneliness is common among both younger and older adults, it is experienced differently across the lifespan and has different antecedents and consequences. The current study measured regional cerebral blood flow (CBF) using pulsed arterial spin labeling imaging. Forty-five older (Mage = 63.4) and forty-four younger adults (Mage = 20.9) with comparable degrees of loneliness were included. Whole-brain voxel-wise analysis revealed a main effect of age (in superior temporal and supramarginal gyri), but no main effect of loneliness. Furthermore, the age effect was only observed among people who reported higher level of loneliness. These regions have previously been implicated in social- and attention-related functions. The moderation of loneliness on age and regional CBF suggests that younger and older individuals present differential neural manifestations in response to loneliness, even with comparable levels of loneliness.