The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions. Although promising therapeutics have been identified using these animal models, with most undergoing significant testing in rodent models, the vast majority of these interventions have failed in human clinical trials. This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models. Large animal models such as non-human primates, sheep, pigs, and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline. The objective of this review is to highlight key characteristics that potentially make these gyrencephalic, large animal ischemic stroke models more predictive by comparing pathophysiological responses, tissue-level changes, and model limitations.