Less than 15% of patients with esophageal squamous cell carcinoma (ESCC) survive five years after the diagnosis. A better understanding of the biology of these tumors and the development of clinical biomarkers is necessary. Autophagy is a physiological mechanism involved in the turnover of cellular components, playing critical roles in cancer. In this study, we evaluated the differential levels of three major autophagy regulators (SQSTM1, MAP1LC3B, and BECN1) in ESCC patients. We associated autophagy with histopathologic features, including the differentiation grade, mitotic rate, inflammation score, and the intensity of tumor-infiltrating lymphocytes. We also assessed the nuclear morphometry of the tumor parenchyma and associated it with autophagy and histopathology. The three markers were significantly increased in ESCC in comparison to control. Based on the mean expression of each protein in the control group, 57% of ESCC patients showed high levels of the three markers, compared to 14% in controls. The most frequent profiles found in ESCC were BECNhigh/MAP1LC3high and BECNhigh/SQSTM1high. Using the TCGA database, we found that the autophagy is upregulated in ESCC. Furthermore, high levels of autophagy markers were associated with poor prognosis. Considering the nuclear morphometry, ESCC samples showed a significant reduction in nuclear area, which strongly correlated negatively with autophagy. Finally, the percentage of normal nuclei was associated with tumor differentiation, while lower levels of SQSTM1 were observed in poorly differentiated tumors. We found that the ESCC progression may involve an increase of autophagy and alterations in the nuclear structure, associated with clinically relevant histopathological features.