Background <p>Non-small cell lung cancer (NSCLC) poses a major threat to human health, METTL3 has been reported to promote numerous tumor development by inhibiting ferroptosis. The aim of the present study was to explore the mechanism of action of METTL3 in NSCLC.</p> Methods <p>The UALCAN online platform was applied to analyze METTL3 and PTEN expression in NSCLC and their relationship with tumor stages. NCI-H23 and NCI-H1975 cells were transfected with sh-METTL3, or oe-METTL3 respectively. Then EdU assay was employed to assess cell proliferation and the transwell assay was employed to assess the ability of cells to migrate and invade. Apoptosis was detected using flow cytometry. In addition, m6A methylation levels, oxidative stress indicators, and Fe²⁺ content were determined. Furthermore, GPX4 and PTEN expression, as well as PI3K and AKT phosphorylation were quantified. Finally, the cells with METTL3 knockdown were further transfected with sh-PTEN.</p> Results <p>METTL3 expression was up-regulated in NSCLC and was closely related to the tumor stages. METTL3 overexpression significantly promoted the malignant phenotype of NSCLC cells, increased the methylation level of m6A mRNA, reduced oxidative stress, inhibited the occurrence of ferroptosis and apoptosis, and led to increased expression of GPX4 and activation of the PTEN/PI3K/AKT pathway. Conversely, METTL3 knockdown produced the opposite effect. Importantly, METTL3 knockdown-induced oxidative stress and ferroptosis in NCI-H23 cells were rescued by sh-PTEN or ferroptosis inhibitor Ferrostatin-1.</p> Conclusion <p>METTL3 may inhibit ferroptosis in NSCLC by activating the PTEN/PI3K/AKT pathway, suggesting that METTL3-mediated PTEN/PI3K/AKT pathway may be a promising therapeutic target for NSCLC.</p>