<p>Disorders of consciousness (DoC) present significant challenges in clinical neurology, particularly when caused by brainstem injury. The brainstem’s role, especially its ascending reticular activating system (ARAS), is crucial for maintaining arousal, a fundamental component of consciousness. However, the precise mechanisms by which brainstem injuries lead to DoC remain incompletely understood, and treatment options are limited. This gap in understanding hampers the development of effective therapies and impedes clinical management of these conditions. Here, we provide a comprehensive review of the latest research on the anatomical, neurochemical, and network-based mechanisms linking brainstem injury to DoC. We focus on the brainstem nuclei and neurotransmitter systems, such as serotonin from the dorsal raphe nucleus, norepinephrine from the locus coeruleus, and dopamine from the ventral tegmental area, highlighting their roles in arousal regulation and brainstem–cortical communication. Furthermore, we explore how disruptions in connectivity between the ARAS and cortical networks, as revealed by advanced neuroimaging techniques like diffusion tensor imaging and functional MRI, correlate with the severity of consciousness impairment. Additionally, we discuss therapeutic strategies, including pharmacological interventions and neuromodulation techniques, which aim to restore consciousness by targeting these disrupted networks. This review advances the field by synthesizing current knowledge on the brainstem’s role in consciousness and highlighting the potential of targeted therapies to improve patient outcomes. By elucidating the mechanisms underlying DoC caused by brainstem injury, this review provides a foundation for future research to develop more effective treatments, ultimately contributing to better clinical management and recovery strategies for patients with DoC.</p>