Infections of the head and neck region most often arise from an odontogenic (dental) source, but they can also arise from non-odontogenic sources such as tonsils, paranasal sinuses, middle ear, salivary glands, developmental cysts, and skin. Severe dental caries, pericoronitis, periodontitis, dental surgery, tonsillitis, sinusitis, penetrating traumatic injuries, otitis media or otitis interna, sialadenitis, and facial acne can cause severe infections that can spread to the deep neck spaces and, sometimes lead to serious complications and occasionally result in death. The clinical manifestations of the infections and related complications vary based on the anatomic origin of the infection and path of spread of the infection. Frequently, individuals with systemic comorbidities, such as diabetes, other immunosuppressive disorders, and substance abuse, and those with limited access to healthcare due to socioeconomic reasons and, poor health literacy may delay seeking care and present with more severe infections. This group of patients are more likely to have life-threatening complications such as airway obstruction, cervical necrotizing fasciitis, descending necrotizing mediastinitis, Lemierre’s syndrome (internal jugular vein thrombosis), pericarditis, thoracic empyema, endocarditis, cavernous sinus thrombosis, orbital apex syndrome, brain abscess, osteomyelitis, sepsis and septic shock, and occasionally death. Fortunately, such complications are less common in the present day. Today, we can diagnose infections more accurately with advanced imaging techniques, manage the airway better with endoscopic airway evaluation and indirect visualization tools for intubation, and provide surgical and medical treatment early with appropriate intravenous antibiotics, fluids, and nutrition. Despite these improvements, life-threatening complications do occur; often, due to delay in presentation, delay in diagnosis, or delay in treatment. Also, inadequate treatment or failure of response to treatment can cause significant morbidity and mortality. In this chapter, the authors have compiled the information from their experience and the numerous published retrospective case series and case reports to provide the reader with the knowledge and tools to avoid and to manage serious life-threatening complications of infections. They discuss the literature on predisposing risk factors, etiology, and review the applied anatomy, clinical and radiographic features, diagnosis, management and prevention of some of the complications of odontogenic, and non-odontogenic infections.