Periodontal disease is multifactorial in its aetiology, which encompasses biopsychosocial contributors, including psychological stress. Gastrointestinal distress and dysbiosis have been associated with several chronic inflammatory diseases yet have rarely been investigated with respect to oral inflammation. Given the implications of gastrointestinal distress on extraintestinal inflammation, this study aimed to evaluate the potential role of such distress as a mediator between psychological stress and periodontal disease. Utilizing a cross-sectional, nationwide sample of 828 adults in the USA generated via Amazon Mechanical Turk, we evaluated data collected from a series of validated self-report psychosocial questionnaires on stress, gut-specific anxiety around current gastrointestinal distress and periodontal disease, including periodontal disease subscales targeted at physiological and functional factors. Structural equation modelling was used to determine total, direct and indirect effects, while controlling for covariates. Psychological stress was associated with gastrointestinal distress (ß = .34) and self-reported periodontal disease (ß = .43). Gastrointestinal distress also was associated with self-reported periodontal disease (ß = .10). Gastrointestinal distress likewise mediated the relation between psychological stress and periodontal disease (ß = .03, p = .015). Given the multifactorial nature of periodontal disease(s), similar results were demonstrated using the subscales of the periodontal self-report measure. Associations exist between psychological stress and overall reports of periodontal disease as well as more specific physiological and functional components. Additionally, this study provided preliminary data supporting the potential mechanistic role that gastrointestinal distress plays in connecting the gut-brain and the gut-gum pathways.