Cancer susceptibility candidate 19 (CASC19) is a novel long non-coding RNA (lncRNA) that has been reported to implicate in the development and therapeutic resistance of various cancers. However, the biological functions and the underlying mechanisms of CASC19 in gastric cancer (GC) remain unclear. In this study, GC-related lncRNAs were screened by lnCAR-database analysis. Based on GEPIA database, GC survival analysis associated with CASC19 was carried out. Quantitative real-time PCR (qRT-PCR) and chromogenic in situ hybridization were adopted to determine the expression level of CASC19. 5-ethynyl-2'-deoxyuridine (EdU) assay, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay and cell cycle assay were used to measure the proliferation capabilities of GC cells. Wound healing assay, transwell migration and invasion assay were performed to detect the metastatic ability of GC cells. Furthermore, subcellular fractionation assay, mass spectrometry, RNA pull-down, RNA immunoprecipitation, western blot and protein stability assay were conducted to investigate the mechanism of CASC19 in GC. Here, we report that CASC19 exerts an oncogenic effect on GC. CASC19 was found to be elevated in GC and overexpression of CASC19 was associated with advanced TNM stage and poor prognosis. Functionally, CASC19 knockdown inhibited GC cells proliferation, migration and invasion, and induced cell cycle arrest. Mechanistically, CASC19 interacted with cAMP response element-binding protein 1 (CREB1) and enhanced its stability by preventing its ubiquitin/proteasome-dependent degradation. In conclusion, these findings suggest that CASC19 may act as a cancer accelerator in GC by regulating CREB1 stability and highlight CASC19 as a potential biomarker and a valuable therapeutic target for advanced GC.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.