Purpose <p>To evaluate the role of oxidative DNA damage, cell proliferation, and apoptosis in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) in patients aged 40 years or younger.</p> Methods <p>Sixty-four OL, twenty-eight OSCC and ten normal oral mucosa (NOM) were subjected to immunohistochemistry evaluation of 8-OhDG, Ki-67, Bax, and Bcl-2 using formalin-fixed, paraffin-embedded tissue sections. For the analysis of immunostaining, the immunoreactive score was used for the 8-OhDG, Bax, and Bcl-2 biomarkers, while the labeling index was calculated for Ki-67 quantification. The Mann-Whitney test and Kruskal-Wallis test were used to compare proteins immunoexpression among groups, as well as to assess the association of these markers with clinicopathological features in OL and OSCC cases.</p> Results <p>A significantly higher Ki-67 label index was observed in OSCC compared to OL (<i>p</i> = 0.001). Suprabasal Ki-67 expression differed significantly between OL and NOM groups (<i>p</i> = 0.047). No differences were found in immunoexpression of 8-OHDdG, Bax and BCL-2 between groups. Among OL cases, a significantly higher 8-OHdG expression was observed in severe dysplasia compared to mild and non-dysplasia (<i>p</i> = 0.039). Larger OL lesions exhibited lower Bax expression compared to lesions measuring less than 2&#xa0;cm (<i>p</i> = 0.035). In OSCC, Bcl-2 expression was significantly higher in plaques than in nodular lesions, regardless of ulceration (<i>p</i> = 0.034).</p> Conclusions <p>The findings of this study reinforce the relevance of Ki-67 as a proliferation marker in the progression of OL among younger individuals. Additionally, oxidative stress may be involved in OED progression in this population. The expression of pro-apoptotic markers in OL cases indicates more active apoptosis in the early stages, while the expression of anti-apoptotic markers in OSCC cases suggests that different clinical patterns may reflect distinct biological behaviors and stages of tumor progression.</p>