Oral mucositis (OM) is a common and impactful toxicity of standard cancer therapy, affecting up to 80% of patients. Its aetiology centres on the initial destruction of epithelial cells and the increase in inflammatory signals. These changes in the oral mucosa create a hostile environment for resident microbes, with oral infections co-occurring with OM, especially at sites of ulceration. Increasing evidence suggests that oral microbiome changes occur beyond opportunistic infection, with a growing appreciation for the potential role of the microbiome in OM development and severity. This review collects the latest articles indexed in the PubMed electronic database which analyse the bacterial shift through 16S rRNA gene sequencing methodology in cancer patients under treatment with oral mucositis. The aims are to assess whether changes in the oral and gut microbiome causally contribute to oral mucositis or if they are simply a consequence of the mucosal injury. Further, we explore the emerging role of a patient’s microbial fingerprint in OM development and prediction. The maintenance of resident bacteria via microbial target therapy is under constant improvement and should be considered in the OM treatment.