BACKGROUND: Previously, anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies have shown limited efficacy in MSI-H/MMR-D endometrial cancer, leading to poor clinical outcomes. The gelsolin superfamily, which includes GSN, SCIN, VILL, VIL1, CAPG, AVIL, SVIL, and FLII, plays crucial roles in cell motility and gene regulation. AIMS: The objective of this study is to explore the potential therapeutic and prognostic implications of the gelsolin superfamily in EC. MATERIALS & METHODS: Data from TCGA, GEPIA, THPA, UALCAN, and Kaplan-Meier plotter databases were analyzed to investigate the expression and clinical relevance of gelsolin superfamily members. Co-expression networks of the gelsolin superfamily were assessed using LinkedOmics, GeneMANIA, and NetworkAnalyst. The relationship between gelsolin superfamily and immune cell infiltration was investigated using TIMER, ImmuCellAI, and GEPIA. RESULTS: We found that high expressions of CAPG, AVIL, and SVIL were associated with poor prognosis, while high expressions of GSN and FLII were linked to better outcomes in EC. Functional enrichment analysis indicated the involvement of gelsolin superfamily members in pathways related to estrogen response, MYC targets, epithelial-mesenchymal transition, TGF beta signaling, MTORC1 signaling, oxidative phosphorylation, inflammatory response, and IL6-JAK-STAT3 signaling. Furthermore, gelsolin superfamily members demonstrated strong correlations with the levels of monocytes, natural killer T, naive CD4+ T, follicular helper T, and central memory T in EC. In vitro studies showed that silencing CAPG and FLII could inhibit proliferation and metastasis in endometrial cancer cell lines. CONCLUSION: These findings indicate the significant association of gelsolin superfamily members with prognosis and immunological status in endometrial cancer.