Background <p>The E3 ubiquitin ligase HECW1 was found to be involved in ubiquitination modifications during malignant progression of multiple tumors. However, the prognostic role of HECW1 expression in gastric cancer (GC) remains unclear.</p> Methods <p>The Tumor Immunoassay Resource (TIMER2.0) system evaluated the association of HECW1 with tumor-infiltrating lymphocytes in carcinomas. The UALCAN assessed HECW1 mRNA expression levels in GC tissues and examined their associations with clinicopathological characteristics. The Kaplan Meier-plotter analyzed the effect of HECW1 on the survival of GC patients. The cBioPortal retrieved information about genetic variants in HECW1 gene. Protein‒protein interaction (PPI) networks associated with HECW1 were explored using the STRING database. The functional effects of HECW1 on GC cells were evaluated through proliferation (Cell Counting Kit-8), apoptosis (Flow cytometry), and migration (Transwell and wound healing assays). The RNA-Seq was applied to explore the underlying mechanisms.</p> Results <p>HECW1 demonstrated significant overexpression in GC tumor tissues, correlating with adverse clinical outcomes. Clinically, elevated HECW1 expression exhibited an inverse association with tumor-infiltrating CD8⁺ T lymphocytes while demonstrating a positive correlation with macrophages, DCs, and neutrophils infiltration, suggesting its potential involvement in tumor immune evasion mechanisms. Functional validation revealed that HECW1 knockdown markedly suppressed GC cell proliferation and migratory capacity, concurrently promoting apoptotic cell death. Mechanistic investigations identified that HECW1 exerts its oncogenic effects through dysregulation of the Hippo signaling pathway, with its silencing effectively attenuating tumor progression via pathway modulation.</p> Conclusions <p>HECW1 upregulation is significantly associated with poor prognosis and immune infiltration in GC patients, emphasizing its potential as a prognostic biomarker.</p>