Neurodegenerative disorders affect more than fifty million Americans each year and represent serious health threats as the population ages. Neuroinflammation and oxidative stress are critical in the onset, progression, and pathogenesis of neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS). A wide range of natural compounds has been investigated because of their antioxidant, anti-inflammatory, and neuroprotective properties. The citrus flavonoid hesperetin (HPT), an aglycone of hesperidin found in oranges, mandarins, and lemons, has been extensively reported to exert neuroprotective effects in experimental models of neurogenerative diseases. This review has compiled multiple studies on HPT in both in vivo and in vitro models to study neurodegeneration. We focused on the modulatory effects of hesperetin on the release of cellular anti-inflammatory and antioxidative stress mediators. Additionally, this review discusses the hesperetin effect in maintaining the levels of microRNA (miRNA) and modulating autophagy as it relates to hesperetin's protective mechanisms against neurodegeneration. Moreover, this review is focused on providing experimental data for hesperetin's potential as a neuroprotective compound and discusses reported evidence that HPT crosses the blood-brain barrier. In summary, this review shows the evidence available in the literature to indicate the efficacy of hesperetin in delaying the onset of neurodegenerative diseases.