<p>Ischemia–reperfusion injury (IRI) is a complex and clinically significant pathophysiological process that occurs when blood flow is restored to an organ following ischemia. While reperfusion is essential for tissue survival, it paradoxically exacerbates damage through mechanisms such as oxidative stress, inflammation, mitochondrial dysfunction, and endothelial injury. This phenomenon contributes significantly to morbidity and mortality in various clinical settings, including organ transplantation, myocardial infarction, stroke, and liver and kidney injuries. Despite increasing knowledge of the molecular pathways involved, effective treatment options remain limited. Recent scientific advances have highlighted the potential of natural bioactive compounds to reduce oxidative and inflammatory responses during IRI. Hass avocado (<i>Persea americana</i> Mill.) has garnered considerable attention as a rich source of phytochemicals with strong antioxidant and anti-inflammatory properties, including carotenoids, tocopherols, polyphenols, and monounsaturated fatty acids (MUFAs). These compounds may act synergistically to neutralize reactive oxygen species, inhibit proinflammatory mediators, and modulate key cellular pathways involved in IRI. This comprehensive review explores the current evidence regarding the protective effects of Hass avocado bioactive compounds against IRI. We examined their molecular mechanisms of action and discussed the therapeutic implications of incorporating these natural agents into clinical practice. To our knowledge, this is the first review specifically addressing the role of Hass avocado phytochemicals in reducing oxidative damage and inflammation in IRI, offering a novel perspective for future research and clinical application.</p> Graphical Abstract <p></p>