Purpose of Review <p>The massive processing of longan fruit consequently generates a significant quantity of by-products that are a nuisance to the environment. This review aims to tap these by-products for sustainable applications in treating hepatic diseases.</p> Recent Findings <p>Ethnobotanical investigations show that longan fruit has been utilized in liver functioning for over two millennia and is supported by contemporary scientific findings. Recent studies highlighted that these by-products contain bioactive compounds that decrease <i>oxidative stress</i> and <i>inflammation</i>, key drivers of liver diseases, including liver fibrosis, hepatitis, and non-alcoholic fatty liver disease (NAFLD). These bioactive compounds modulate lipid metabolism, <i>detoxification pathways</i>, and oxidative stress-regulating metabolic pathways of <i>hepatoprotection</i>. In addition, using longan by-products provides a relatively more affordable nutraceutical substitute for synthetic pharmaceuticals.</p> Summary <p>This literature revealed that polyphenolic compounds such as <i>corilagin gallic acid</i>, <i>ellagic acid</i>, and various flavonoids in longan by-products exhibit <i>antioxidant</i>, <i>anti-inflammatory</i>, <i>and immunomodulatory</i> activities that benefit liver health through different pathways including unexplored mechanisms. However, this review recommends exploring the potential <i>functional application</i> of these by-products in food. It emphasizes the need for clinical validation of longan by-product therapies for <i>liver diseases</i>.</p>