Objective: This study aims to explore the correlation between the expression of mutant p53 protein and cellular atypia in early differentiated gastric adenocarcinoma (DGA). Methods: A total of 107 cases of early DGA samples resected by endoscopic submucosal dissection (ESD) were collected from the Pathology Department of Beijing Friendship Hospital from January 2018 to December 2019. The EnVision two-step immunohistochemical method was used to detect the expression of mutant p53 protein in these cancer tissues, and the correlation with cell atypia was analyzed. Results: In early DGA tissues, the expression rate of mutant p53 protein was significantly higher than in normal gastric mucosa (P < 0.01). However, the expression of mutant p53 protein was not correlated to age or gender (P > 0.05) but to the location of the tumor, depth of invasion, and degree of differentiation (P < 0.01). The expression of mutant p53 protein was closely correlated to cell atypia. Furthermore, this was weakly positive in low-grade atypical adenocarcinoma but strongly positive or negative in high-grade atypical adenocarcinoma, and there was a significant difference between these two (P < 0.01). Conclusion: Mutant p53 protein is highly expressed in early DGA, which can be used as an auxiliary index for the diagnosis of early gastric cancer. The different expression patterns of mutant p53 protein in high-grade and low-grade atypical gastric cancers suggest that these may have different genetic changes.