<p>Atypical oxytocinergic functioning and altered microbiome compositions have both been implicated in autism, with growing evidence of interactions between these systems. However, how exogenous oxytocin influences the oral microbiome remains largely unexplored. This exploratory study examined for the first time how oral microbiome alterations link to oxytocinergic signalling in school-aged autistic (<i>n</i> = 80) and non-autistic children (<i>n</i> = 40). Additionally, we investigated the effect of four-weeks of intranasal oxytocin administration in autistic children on oral microbiome compositions immediately post-treatment (T1) and at four-weeks follow-up (T2). At baseline, lower endogenous salivary oxytocin levels were linked to greater microbial evenness and diversity, with twelve genera showing significant associations with oxytocin levels. In autistic children, four weeks of oxytocin administration was associated with significant increases in the abundances of <i>Centipeda</i> immediately post-treatment (T0-T1), alongside decreases in <i>Moraxella</i> (T0-T1), and subsequent reductions in <i>Rothia</i> observed at the four-week follow-up (T1-T2). Particularly, the genus <i>Moraxella</i> emerged as relevant, as lower baseline abundance was associated with higher endogenous oxytocin levels, and a stronger oxytocin-induced downregulation of its abundance correlated with greater increases in endogenous oxytocin levels, accompanied by hypomethylation of the oxytocin receptor gene. All results persisted after adjusting for nutrition and dental care. This exploratory study provides initial evidence for a role of the oxytocinergic system in shaping the oral microbiome in autistic children. These results may facilitate the integration of oral microbiome profiling into autism diagnostic criteria and stimulate future studies on the use of oxytocin as a therapeutic option targeting oral microbiome alterations.</p>