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The role of dysbiosis in the development and progression of oral potentially malignant disorders (OPMDs) remains largely unknown. Here, we aim to characterize and compare the oral microbiome of homogeneous leucoplakia (HL), proliferative verrucous leukoplakia (PVL), oral squamous cell carcinoma (OSCC), and OSCC preceded by PVL (PVL-OSCC). Fifty oral biopsies from HL (<i>n</i> = 9), PVL (<i>n</i> = 12), OSCC (<i>n</i> = 10), PVL-OSCC (<i>n</i> = 8), and healthy (<i>n</i> = 11) donors were obtained. The sequence of the V3–V4 region of the 16S rRNA gene was used to analyze the composition and diversity of bacterial populations. In the cancer patients, the number of observed amplicon sequence variants (ASVs) was lower and <i>Fusobacteriota</i> constituted more than 30% of the microbiome. PVL and PVL-OSCC patients had a higher abundance of <i>Campilobacterota</i> and lower <i>Proteobacteria</i> than any other group analyzed. A penalized regression was performed to determine which species were able to distinguish groups. HL is enriched in <i>Streptococcus parasanguinis</i>, <i>Streptococcus salivarius</i>, <i>Fusobacterium periodonticum</i>, <i>Prevotella histicola</i>, <i>Porphyromonas pasteri</i>, and <i>Megasphaera micronuciformis</i>; PVL is enriched in <i>Prevotella salivae, Campylobacter concisus, Dialister pneumosintes</i>, and <i>Schaalia odontolytica</i>; OSCC is enriched in <i>Capnocytophaga leadbetteri, Capnocytophaga sputigena, Capnocytophaga gingivalis, Campylobacter showae, Metamycoplasma salivarium</i>, and <i>Prevotella nanceiensis</i>; and PVL-OSCC is enriched in <i>Lachnospiraceae bacterium, Selenomonas sputigena</i>, and <i>Prevotella shahii</i>. There is differential dysbiosis in patients suffering from OPMDs and cancer. To the best of our knowledge, this is the first study comparing the oral microbiome alterations in these groups; thus, additional studies are needed.