Objective To investigate the clinicopathological significance of the overexpression of Mortalin protein in endometrial carcinoma (EC). Methods Mortalin expression was evaluated in 88 EC samples and 37 paracarcinoma tissue samples by immunohistochemical (IHC) staining. The expression of Mortalin mRNA in EC tissues was analyzed by UALCAN database. Correlations between Mortalin overexpression and clinicopathological features of EC patients were analyzed. Overall survival rate of EC patients was performed based on The Human Protein Atlas and The Cancer Genome Atlas (TCGA) databases. Results Mortalin showed a cytoplasmic staining pattern in EC. The positive rate and strongly positive rate of Mortalin in EC were 88.6% (78/88) and 56.8% (50/88), which were both significantly higher compared with para-carcinoma tissues (P < 0.05). Mortalin overexpression was positively correlated with the pathological grade, TNM stage and LN metastasis in EC (P < 0.05), while it had no statistical significance with age (P > 0.05). The UALCAN database noted that the expression of Mortalin mRNA was elevated in EC tissues compared with that observed in paracarcinoma tissue samples. Additionally, The Human Protein Atlas and TCGA database showed that the patients with high Mortalin expression had poorer prognosis than those with low Mortalin expression (P <0.05). Conclusion Mortalin high expression is significantly associated with tumorigenesis, cancer progression and the prognosis of EC patients, which may serve as an important indicator for target therapy and prognosis evaluation in EC.