Background/Objectives: Oral leukoplakia (OLK) is an oral mucosal lesion classified in the oral potentially malignant disorder group and is associated with an increased risk of malignant transformation (MT). The aim of this study was to compare the clinical and histopathological features of two OLK groups, a group of smokers and a group of non-smokers. Methods: In this retrospective study, a cohort of 154 patients with OLK was divided into two groups based on the presence of smoking as a major risk factor. OLK diagnoses were established via clinical and histopathological examination. Results: Females were more abundant in the non-smoking group than in the smoking group, where males were more abundant (p < 0.001). The average age of the smokers was lower than that of the non-smokers (p = 0.003). In the smokers, the buccal mucosa was most frequently affected, while in the non-smokers, the gums and the tongue were primarily involved (p = 0.016). In female smokers, involvement of the buccal area and multiple-site involvement were statistically significantly more frequently observed compared to that in female non-smokers (p = 0.006). Non-dysplastic lesions were predominant in both groups, with severe dysplasia observed more frequently in the non-smokers than in the smokers. MT was higher in the non-smoker group compared to that in the smoker group. Conclusions: OLK in smokers is different from OLK in non-smokers concerning female gender involvement, site location, the number of lesions, and the MT rate.