Diffuse cortical diffusion changes on magnetic resonance imaging (MRI) are characteristically ascribed to global cerebral anoxia, typically after cardiac arrest. Far from being pathognomonic, however, this neuroimaging finding is relatively nonspecific, and can manifest in a myriad of disease states including hypoxia, metabolic derangements, infections, seizure, toxic exposures, and neuroinflammation. While these various conditions can all produce a neuroimaging pattern of widespread cortical diffusion restriction, many of these underlying causes do have subtly unique imaging features that are appreciable on MRI and can be of clinical and diagnostic utility. Specific populations of neurons are variably sensitive to certain types of injury, whether due to differences in perfusion, receptor type density, or the unique tropisms of infectious organisms. In this narrative review, we discuss a number of distinct etiologies of diffuse cortical diffusion restriction on MRI, the unique pathophysiologies responsible for tissue injury, and the resulting neuroimaging characteristics that can be of assistance in differentiating them. As widespread cortical injury from any cause often presents with altered mental status or coma, the differential diagnosis can be enhanced with rapid acquisition of MRI when clinical history or detailed physical examination is limited. In such settings, the distinct imaging features discussed in this article are of interest to both the clinician and the radiologist.