Interleukin-1β (IL-1β) is a potent proinflammatory cytokine that is mainly produced by microglia in the central nervous system. It is considered to act as a key mediator of inflammatory processes not only in physiological conditions, but also during various pathological conditions, such as infection, injury, ischemia, and neurodegeneration. The mechanism through which such a leaderless protein is transferred from the cytoplasm to the extracellular space is an important unresolved issue in the study of IL-1β biology. Emerging evidence suggests that autophagy plays an important role in the unconventional secretion of IL-1β. Autophagy might negatively regulate IL-1β expression by lysosomal degradation, while mature IL-1β could be secreted by an autophagy-based Golgi reassembly stacking protein (GRASP)-dependent secretory pathway. We also found that activation of the P2X7 receptor (P2X7R), an ATP-gated cation channel, plays a critical role in the regulation of basal autophagy flux as well as the maturation and unconventional secretion of IL-1β in microglial cells. Taken together, better understanding of the role of the autophagy-lysosomal pathway in the maturation and secretion of IL-1β in microglia might provide a new strategy for targeting neuroinflammation in various pathological conditions.