The 5‑year survival rate of patients with esophageal squamous cell carcinoma (ESCC) is <
20%, highlighting the need for the development of novel therapeutic targets. Neuregulin‑1 (NRG1), a transmembrane protein involved in cell proliferation and survival signaling, has unclear biological functions and clinical value in ESCC. The present study investigated the association between NRG1 expression and ESCC by analyzing data from both patients with ESCC and The Cancer Genome Atlas database. Reverse transcription‑quantitative PCR and immunohistochemistry staining were used to determine the levels of gene and protein in the tissue. The findings revealed that NRG1 gene and protein levels were significantly higher in tumor tissues compared with the normal tissues. Elevated expression of NRG1 was associated with poor outcomes, particularly in patients with advanced ESCC. Silencing NRG1 decreased both its mRNA and protein levels, disrupting key signaling pathways, such as phosphorylated (p‑)AKT and cellular rapidly accelerated fibrosarcoma (p‑cRAF), which led to decreased cancer cell proliferation, migration and tumor sphere formation, along with increased cell death. High expression levels of NRG1 and cRAF were significantly associated with poor prognosis. Additionally, silencing NRG1 promoted autophagosome and autolysosome formation, decreasing LC3B levels. The use of the autophagy inhibitor chloroquine significantly enhanced cell death induced by NRG1 silencing, suggesting that autophagy functions as a survival mechanism in ESCC cells in which NRG1 is silenced. Furthermore, high co‑expression of NRG1 and LC3B was associated with a worse prognosis. On the whole, the present study demonstrated that targeting NRG1 with autophagy inhibitors may serve as a potential therapeutic strategy for ESCC.