Sleep loss increases the experience of pain. However, the brain mechanisms underlying altered pain processing following sleep deprivation are unknown. Moreover, it remains unclear whether ecologically modest night-to-night changes in sleep, within an individual, confer consequential day-to-day changes in experienced pain. Here, we demonstrate that acute sleep-deprivation amplifies pain reactivity within human (male and female) primary somatosensory cortex yet blunts pain-reactivity in higher-order valuation and decision-making regions of the striatum and insula cortex. Consistent with this altered neural signature, we further show that sleep deprivation expands the temperature range for classifying a stimulus as painful, specifically through a lowering of pain thresholds.