PURPOSE: Among malignant tumors, non-small cell lung cancer (NSCLC) remains a major threat to human life and health. Studies have illustrated that minichromosome maintenance protein 4 (MCM4) has complex interactions with the progression of many cancers, yet the role and mechanism of MCM4 in NSCLC remain to be elucidated. METHODS: MCM4 expression in NSCLC tissues was assessed using the TCGA database. MCM4 levels in NSCLC cells and tissues was validated utilizing qRT-PCR and western blot. Cell proliferation, metastasis and EMT were measured by CCK-8, transwell, and western blot assays. Subsequently, E2F1 bound with the promoter of MCM4 was predicted via JASPAR database. Luciferase assay and chromatin immunoprecipitation (ChIP) were utilized to evaluate the binding relationship between the two. Finally, rescue experiments were performed to demonstrate the mechanism of MCM4 regulating NSCLC progression. Xenograft model was utilized to prove the role of MCM4 and E2F1 in NSCLC in vivo. RESULTS: MCM4 was markedly elevated in NSCLC tumor samples and intimately linked to poor patient prognosis. Silencing of MCM4 repressed growth, migration, invasion, and EMT of cells. In vivo test findings displayed that knockdown of MCM4 suppressed changes in tumor volume and weight in mice. Moreover, E2F1 bound with the promoter of MCM4 was predicted by JASPAR database. E2F1 was heightened in NSCLC tissues and cells. Then, the outcome of rescue assays confirmed that E2F1 introduction attenuated the depressing influence of MCM4 knockdown on NSCLC. Moreover, E2F1/MCM4 promoted the progression of NSCLC by activating the PI3K/AKT signaling pathway. CONCLUSIONS: E2F1 accelerated NSCLC progression by activating the PI3K/AKT pathway through MCM4. Our outcomes confirmed that MCM4 is a potential target for the treatment of NSCLC patients.