Objective To investigate the expression changes of Smad homolog 4 (SMAD4), sex-determining region Y-box protein 2 (SOX2), and P53 gene (P53) in cancer tissues of patients with cervical cancer (CCA), as well as their predictive value for prognosis. Methods A total of 82 patients with CCA admitted to Luohe Central Hospital from January 2021 to January 2022 were retrospectively selected, serving as the observation group, and another 82 patients with benign tumors were selected as the control group. The expression levels of SMAD4, SOX2, and P53 were compared between the two groups with different pathological characteristics. The correlation between each indicator and the pathological characteristics of CCA was analyzed, and the relationship between these indicators and the prognosis of CCA patients was explored. Results The expression levels of SOX2 and P53 in the observation group were higher than those in the control group, while the expression level of SMAD4 was lower (P<0.05). The expression levels of SOX2 and P53 in patients with stages Ⅰ-Ⅱ were lower than those in patients with stages Ⅲ-Ⅳ, and those in high-differentiated patients were lower than those in moderately and low differentiated patients. The expression level of SMAD4 was higher in patients with stages Ⅲ-Ⅳ than in patients with stages Ⅰ-Ⅱ, and higher in well-differentiated patients than in moderately and poorly differentiated patients (P<0.05). The expression of SOX2 and P53 in CCA patients was positively correlated with TNM staging and negatively correlated with differentiation degree, while the expression of SMAD4 was negatively correlated with TNM staging and positively correlated with differentiation degree (P<0.05). The 2-year survival rate of patients with positive SOX2 and P53 expression was lower than that of patients with negative expression, while the 2-year survival rate of patients with positive SMAD4 expression was higher than that of patients with negative expression (P<0.05). Conclusion In CCA tissues, there is an abnormal increase in the expression of SOX2 and P53, and an abnormal decrease in the expression of SMAD4. These three indicators are closely related to the occurrence, TNM staging, and differentiation degree of CCA, and can provide effective references for clinical prognosis prediction.