<p>Anoikis is a form of apoptosis induced by cell detachment from the extracellular matrix, and cancer cells must evade it to metastasize. Gastric cancer (GC) remains a leading global cause of cancer-related mortality, with intestinal metaplasia (IM) established as a key premalignant lesion. This study explored the multi-omics features of the anoikis-related gene <i>SPP1</i> across the control-IM-GC cascade, focusing on its links to immunity and prognosis. Comprehensive transcriptome analyses were conducted using datasets from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the GeneCards database via the R programming language. By integrating Weighted Gene Co-expression Network Analysis (WGCNA) and competing endogenous RNA (ceRNA) networks, alongside Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA), the study explored the immunological roles of Secreted Phosphoprotein 1 (SPP1) in GC. Furthermore, immune infiltration and immune checkpoint analyses were combined with single-cell RNA sequencing (scRNA-seq) to elucidate the tumor microenvironment. Finally, Cox proportional hazards regression and Receiver Operating Characteristic (ROC) curve analyses were utilized to assess the prognostic significance of SPP1 and to construct a predictive risk signature. RT-qPCR/Western blot (32 human tissues) and in vitro assays were conducted to validate SPP1’s expression and function. SPP1 was significantly upregulated across the Correa cascade, with high predictive accuracy, and was associated with survival and potential immunotherapy relevance. Higher levels were associated with a poorer prognosis. In vitro, SPP1 inhibition reduced GC cell migration, enhanced apoptosis, and induced S/G2 phase arrest. To our knowledge, this is the first study to associate SPP1 with IM/GC. Our findings suggest that it may serve as a prognostic biomarker, with immunotherapeutic implications that require further study.</p>