Development of new non-addictive analgesics would greatly benefit from directed differentiation of hPSCs into relevant cell types. Here, we devised a highly efficient step-wise protocol that differentiates human pluripotent stem cells (hPSCs) exclusively into nociceptors under fully defined conditions. By manipulating critical cell signaling pathways using small molecule inhibitors, hPSCs were first converted into SOX10+ neural crest stem cells followed by differentiation into bona fide nociceptors. Time-course RNA-Seq analysis (Day 0-28) and immunocytochemistry experiments confirmed that nociceptors expressed typical neuronal markers, transcription factors, neuropeptides, and ion channels. Focusing on pain-relevant receptors expressed by hPSC-derived nociceptors (e.g. P2RX3, opioid receptors), we could demonstrate robust functional activities in multi-electrode array experiments and differential responses to nociceptive stimuli and specific drugs including natural and synthetic opioids. The nociceptor differentiation protocol was then automated by using a robotic cell culture system (CompacT SelecT^TM) enabling multiple high- throughput projects that require large numbers of cells. In summary, the scalable human nociceptor platform developed here will aid in the discovery of new pain medications as part of the effort to tackle the opioid crisis.