Hypoxia is a typical hallmark of solid tumors and plays a crucial role in the progression of esophageal squamous cell carcinogenesis (ESCC). Nevertheless, the precise mechanisms underlying the involvement of hypoxia in tumor development remain unclear. In the present study, a novel hypoxia-induced long noncoding RNA (lncRNA) is identified first, lnc191, which is highly expressed in clinical ESCC tissues and is positively correlated with poor prognosis of ESCC patients. These findings provide evidence that the hypoxia-inducible factor-1 alpha (HIF-1 alpha)-mediated transcriptional activation of lnc191 enhances the growth and metastasis of ESCC cells both in vitro and in vivo. Mechanistically, lnc191 interacts with GRP78 (78-kDa glucose-regulated protein), one of the endoplasmic reticulum chaperone proteins, leading to its translocation to the membrane, where GRP78 binds with EGFR and enhances its phosphorylation (Y845), further activates ERK/MAPK signaling pathway, and thereby in favor of the progression of ESCC. Overall, this data proposes lnc191 as a key driver during the development of ESCC and reveals the participation of the activated GRP78/ERK/MAPK axis in the ESCC progression mediated by lnc191. These findings indicate the potential of lnc191 as a promising diagnostic biomarker and therapeutic target in ESCC.