Radiation therapy is an essential component of multimodality cancer treatment, as it can potentially eliminate tumors and improve patient outcomes. However, radiation therapy may induce severe side effects, such as highly debilitating radiation-induced trismus. Radiation-induced trismus, characterized by restricted jaw movement and muscular rigidity, represents a severe challenge in cancer treatment and may threaten an affected patient’s life in certain conditions like emergencies. The medical literature has researched and documented the mechanisms that cause radiation-induced trismus, a hyperinflammatory disease, by inducing and maintaining inflammation after head and neck irradiation. Significant labor has been undertaken to elucidate the series of events that play crucial roles in the development and progression of this unfortunate condition, with particular emphasis on critical factors such as oxidative stress, cytokine dysregulation, damage to salivary glands and soft tissues, and the triggers of a hyper-inflammatory state. However, too many unknowns remain about the exact relationship between radiation-induced trismus and hyperinflammation caused by head and neck irradiation. Hence, this chapter aims to provide an evidence-based review of the intricate and multifaceted interactions between radiation-induced hyperinflammation and the development of radiation-induced trismus in head and neck cancer patients treated with radiation or chemoradiotherapy.