Background: The voltage-dependent anion channel 1 protein (VDAC1) plays a role in cellular metabolism and survival. It was found to be down or upregulated (overexpressed) in different malignancies but it was never studied in application to oral lesions. The purpose of this study was to retrospectively evaluate the expression of VDAC1 in biopsies of oral premalignant, malignant, and malignancy-neutral lesions and to examine the possible correlations to their clinicopathological parameters. Materials and methods: 103 biopsies including 49 oral squamous cell carcinoma, 33 epithelial dysplasia, and 21 fibrous hyperplasia samples were immunohistochemically stained with anti-VDAC1 antibodies for semi-quantitative evaluation. The antibody detection was performed with 3,3′-diaminobenzidine (DAB). The clinicopathological information was examined for possible correlations with VDAC1. Results: VDAC1 expression was lower in oral squamous cell carcinoma 0.63 ± 0.40 and in oral epithelial dysplasia 0.61 ± 0.36 biopsies compared to fibrous hyperplasia biopsies 1.45 ± 0.28 (p < 0.01 for both; Kruskal–Wallis test). Conclusion: Oral squamous cell carcinoma and epithelial dysplasia tissues demonstrated decreased VDAC1 protein expression if compared to fibrous hyperplasia samples, but were not different from each other, suggesting that the involvement of VDAC1 in oral carcinogenesis is an early stage event, regulating cells to live or die.