Most hereditary periodic fever syndromes are mediated by deregulated IL-1β secretion. The generation of mature IL-1β requires two signals: one that induces synthesis of inflammasome components and substrates, and a second that activates inflammasomes. The mechanisms that mediate autoinflammation in mevalonate kinase deficiency (MKD), a periodic fever disease characterized by a block in isoprenoid biosynthesis, is poorly understood. In studying the effects of isoprenoid shortage on IL-1 β generation, we identified a new inflammasome activation signal that originates from defects in autophagy. We find that hyper-secretion of IL-1β and IL-18 requires reactive oxygen species (ROS) and is associated with an oxidized redox status of monocytes, but not lymphocytes. IL-1β hyper-secretion by monocytes involves decreased mitochondrial stability, release of mitochondrial content into the cytosol and attenuated autophagosomal degradation. Defective autophagy, as established by ATG7 knockdown, results in prolonged cytosolic retention of damaged mitochondria and increased IL-1β secretion. Finally, activation of autophagy in healthy but not MKD patient cells reduces IL-1β secretion. Together these results indicate that defective autophagy can prime monocytes for mitochondria-mediated NLRP3 inflammasome activation, thereby contributing to hyper-secretion of IL-1β in mevalonate kinase deficiency.