Background: Obstructive sleep apnea (OSA) patients commonly experience high rates of depression. This study aims to examine the oral microbiota characteristics of OSA and those with comorbid major depressive disorder (OSA+MDD) patients. Methods: Participants were enrolled from Aug 2022 to Apr 2023. Polysomnography, psychiatrist interviews, and scales were used to diagnose OSA and MDD. Oral samples were collected from participants by rubbing swabs on buccal mucosa, palate, and gums. Oral microbiota was analyzed via whole-genome metagenomics and bioinformatic analysis followed sequencing. Venous blood was drawn to detect plasma inflammatory factor levels. Results: The study enrolled 33 OSA patients, 28 OSA+MDD patients, and 28 healthy controls. Significant differences were found in 8 phyla, 229 genera, and 700 species of oral microbiota among the three groups. Prevotellaceae abundance in the OSA and OSA+MDD groups was significantly lower than that in healthy controls. Linear discriminant analysis effect size (LEfSe) analysis showed that Streptococcaceae and Actinobacteria were the characteristic oral microbiota of the OSA and OSA+MDD groups, respectively. KEGG analysis indicates 30 pathways were changed in the OSA and OSA+MDD groups compared with healthy controls, and 23 pathways were changed in the OSA group compared with the OSA+MDD group. Levels of IL-6 in the OSA+MDD group were significantly higher than in the healthy group, correlating positively with the abundance of Schaalia, Campylobacter, Fusobacterium, Alloprevotella, and Candidatus Nanosynbacter in the oral, as well as with Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale scores. Conclusion: Significant differences in oral microbiota populations and gene function were observed among the three groups. OSA patients were characterized by a decreased abundance of Prevotellaceae and an increased abundance of Streptococcaceae. OSA+MDD patients had an increased abundance of Actinobacteria. IL-6 might regulate the relationship between depression and the oral microbiota in OSA+MDD patients.