Abstract Aberrant methylation of the EphA7 promoter has been observed in cervical cancer (CC); however, its precise function and role in CC remain largely unknown. In this study, we investigated the role and molecular mechanisms of EphA7 promoter methylation in cervical carcinogenesis. First, our results indicated that the reactivation of EphA7 expression via a CRISPR demethylation tool (dCas9-Tet1) had antitumor effects. It restrained tumor proliferation and invasion while promoting apoptosis via the PI3K/AKT signaling pathway in both CaSki and SiHa cells. The upstream interacting factors were subsequently captured by CRISPR-mediated pull-down in situ, and the result revealed that SP1 and MAZ interacted with the promoter of EphA7. However, the perturbation results revealed that EphA7 expression was associated with SP1/DNMT1 but not MAZ. Furthermore, 17-β-estradiol (E2) can upregulate EphA7 expression through demethylation via the SP1/DNMT1 axis. A rescue experiment revealed that interference with SP1 expression could restore the effect of E2 on increasing the expression of EphA7 by upregulating estrogen receptor expression. In addition, EphA7 demethylation reduced the half-maximal inhibitory concentration (IC50) of cisplatin and paclitaxel. Pooled analysis revealed that EphA7 promoter hypermethylation was positively correlated with tumor purity but negatively correlated with immune cell infiltration, cytotoxic T lymphocyte (CTL) and immune checkpoint (IC) activity, and the expression of EphA7 was significantly positively correlated with tumor mutational burden (TMB), microsatellite instability (MSI) and the presence of single nucleotide variant (SNV) neoantigens, suggesting a better prognosis for patients with EphA7 promoter hypomethylation and high expression. Collectively, these findings indicate that targeted demethylation of the EphA7 promoter and restoration of endogenous EphA7 expression by dCas9-Tet1 are promising therapeutic approaches and are favorable for the prognosis of CC patients.