<p>Background: SERPINB5, also known as Maspin, is a non-inhibitory member of the serine protease inhibitor superfamily. SERPINB5 exerts diverse effects on a variety of human cancers, including cell proliferation, angiogenesis, apoptosis, tumor invasion, and metastasis. SERPINB5 has traditionally been regarded as a tumor suppressor gene, but emerging evidences supports its oncogenic properties. Methods: We conducted a comprehensive review of the existing literature on SERPINB5 in gastrointestinal cancers, synthesizing data on its expression patterns, subcellular localization, epigenetic modifications, and clinical significance. Results: Depending on its subcellular localization and epigenetic modifications, SERPINB5 demonstrate either protumor or antitumor activity in different gastrointestinal cancers, such as colorectal cancer, gastric cancer, pancreatic cancer, gallbladder cancer and liver cancer. We elucidate its potential as a predictive and prognostic biomarker, with a focus on its implications for diagnosis, prognosis, and therapeutic intervention, emphasizing its utility in early lesion detection and treatment. Conclusions: SERPINB5 plays a complex and context-dependent role in gastrointestinal cancers, highlighting further research to dissect the true significance of SERPINB5 expression and the molecular mechanisms underlying its divergent clinical behaviors in cancer.</p> Graphical abstract <p></p>