Radiotherapy- or chemotherapy-induced oral mucositis (RIOM/CIOM) presents significant challenges in cancer treatment, severely impacting patients' quality of life (QoL) and therapeutic outcomes. Despite advancements, existing prevention and treatment measures have notable limitations. RIOM/CIOM involves a multifaceted interplay of inflammatory cascades orchestrated by the innate immune response. Furthermore, dysbiosis of oral and intestinal microbiota, triggered by anticancer therapy, exacerbates mucosal damage through intricate interactions with the innate immune system. This review provides an update on pivotal signaling pathways governing the initiation and progression of RIOM/CIOM. It also elucidates the intricate relationship between microbiota dysbiosis and dysregulation of oral mucosal immune homeostasis. Moreover, potential interventions targeting these pathogenic mechanisms are summarized, offering valuable insights for further exploration of RIOM/CIOM's complex pathophysiology and the development of more effective interventions.