Background <p>Colorectal cancer (CRC), a complex and multifactorial disease, has been associated with elevated expression of microRNA miR-182-5p, although its precise regulatory role in CRC progression remains unclear. This study aims to identify potential therapeutic targets to improve clinical outcomes and to decipher the intricate role of miR-182-5p in the pathobiology of CRC.</p> Methods <p>We conducted comprehensive bioinformatics analyses using GEO databases to investigate differences in miRNA expression between CRC and normal tissues, with a particular focus on miR-182-5p. Its expression levels in CRC cells and tumor tissues were quantified by quantitative real-time PCR (qRT-PCR). The expression of neurocalcin delta (NCALD) and proteins related to Wnt/β-catenin signalling was evaluated by qRT-PCR and Western blotting. Pathological changes in tumor-bearing mice as well as the proliferation, invasion, and migration of CRC cells, were assessed. Tumor cell proliferation and apoptosis were examined using Ki-67 immunohistochemistry and TUNEL staining, respectively. A dual luciferase reporter assay explored the regulatory interaction between miR-182-5p and NCALD.</p> Results <p>Our findings reveal significantly elevated miR-182-5p levels in CRC tissues and cell lines, positively correlated with tumor invasion depth, differentiation degree, clinical stage, and lymph node metastasis. miR-182-5p appears to accelerate CRC progression in both cell lines and mouse models by downregulating NCALD, thereby enhancing Wnt/β-catenin signalling. This study identifies miR-182-5p as a pivotal enhancer of CRC progression, modulating Wnt/β-catenin signalling via NCALD regulation.</p> Conclusions <p>The findings position the miR-182-5p/NCALD axis as promising targets for CRC therapy, offering new avenues for treatment strategies.</p> <p><i>Trial registration:</i> Retrospectively registered.</p>