Small nucleolar RNAs (snoRNAs) are an important group of non-coding RNAs that have been reported to play a key role in the occurrence and development of various cancers. Here we demonstrate that Small nucleolar RNA 42 (SNORA42) enhanced the proliferation and migration of Oesophageal squamous carcinoma cells (ESCC) via the DHX9/p65 axis. Our results found that SNORA42 was significantly upregulated in ESCC cell lines, tissues and serum of ESCC patients. The high expression level of SNORA42 was positively correlated with malignant characteristics and over survival probability of patients with ESCC. Through in vitro and in vivo approaches, we demonstrated that knockdown of SNORA42 significantly impeded ESCC growth and metastasis whereas overexpression of SNORA42 got opposite effects. Mechanically, SNORA42 promoted DHX9 expression by attenuating DHX9 transports into the cytoplasm, to protect DHX9 from being ubiquitinated and degraded. From the KEGG analysis of Next-Generation Sequencing, the NF-κB pathway was one of the most regulated pathways by SNORA42. SNORA42 enhanced phosphorylation of p65 and this effect could be reversed by NF-κB inhibitor, BAY11-7082. Moreover, SNORA42 activated NF-κB signaling through promoting the transcriptional co-activator DHX9 interacted with p-p65, inducing NF-κB downstream gene expression. In summary, our study highlights the potential of SNORA42 is up-regulated in ESCC and promotes ESCC development partly via interacting with DHX9 and triggering the DHX9/p65 axis.Copyright © 2018. Published by Elsevier Inc.