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Simple Summary: This research leveraged three-dimensional confocal imaging to examine elafin's spatial distribution in locoregional esophageal squamous cell carcinoma (ESCC) tumors. Our findings highlighted distinct elafin localizations in patients with poor versus favorable prognoses. Elafin expression was significantly higher in tumor regions, contributing to a poorer prognosis. Complementary in vitro studies revealed that elafin promotes ESCC cell proliferation, migration, and invasion via the epithelial–mesenchymal transition pathway. These findings suggest that the targeted inhibition of elafin could potentially serve as a novel therapeutic approach aimed at improving survival rates in patients with locoregional ESCC. Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data obtained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I–IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial–mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC. [ABSTRACT FROM AUTHOR]