<p><b>Background</b>. Oral leukoplakia (OLK) is the most prevalent potentially malignant oral disorder (OPMD). Ferroptosis, a distinct form of regulated cell death, has recently garnered significant attention in a variety of diseases. DIRAS2 is a member of the DIRAS family within the RAS protein superfamily and is highly expressed in OLK tissues. Nevertheless, the precise mechanism through which DIRAS2 modulates ferroptosis in OLK remains elusive. <b>Methods</b>. Immunohistochemical staining was used to assess the expression of GPX4 in human normal oral mucosa and OLK tissues. DIRAS2 knockdown and control Leuk-1 cell were treated with Erastin to induce ferroptosis, and EDU, Mito Tracker green and MitoSOX probes were utilized to evaluate cell proliferation and mitochondrial changes. Additionally, the expression of ferroptosis-associated proteins and PI3K-AKT pathway in Leuk-1 cells and 4-nitroquinoline-1-oxide (4NQO)-induced DIRAS2^flox/flox mouse and DIRAS2^{flox/flox:Cre+} mouse tongue tissues was examined via western blotting and immunohistochemistry, respectively. <b>Results</b>. GPX4 was abnormally highly expressed in human OLK tissues than in normal mucosa tissues. Erastin significantly elevated Reactive Oxygen Species (ROS) level in Leuk-1 cells, concurrently downregulating cell proliferation and GPX4, PI3K, AKT and pAKT expression. DIRAS2 knockdown further potentiated Erastin-induced ferroptosis. Additionally, compared with the control group, DIRAS2-knockdown cells presented significant alterations in mitochondrial morphology. Compared to control mice, the expression of GPX4, PI3K, AKT and pAKT in the 4NQO-induced mouse tongue tissues was markedly upregulated. The expression of these proteins in DIRAS2^{flox/flox:Cre&#xa0;+} mouse tongue tissues demonstrated a notable reduction compared with DIRAS2^flox/flox mouse tongue tissues. <b>Conclusion</b>. DIRAS2 may affect OLK development by repressing ferroptosis through the PI3K/AKT pathway.</p>