Autoimmune diseases are characterized by an exacerbated immune response against the body's own tissues. The main pathologies include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis and inflammatory bowel disease. All these pathologies are based on oxidative stress and chronic inflammation. Therefore, the search for alternative therapies based on natural compounds with antioxidants, anti-inflammatory and immunomodulatory properties has become highly relevant in biomedical research. In this sense, polyphenols extracted from the skin of green kiwi (Actinidia deliciosa) have shown beneficial effects in the regulation of the immune system. This review aims to describe how polyphenols extracted from the skin of green kiwi interact with key enzymes and proteins in the human body to reach their therapeutic target. In this sense, kiwi polyphenols can exert positive effects on autoimmune diseases due to their ability to modulate proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). On the other hand, kiwi polyphenols can act as potent scavengers of reactive oxygen species (ROS), reducing oxidative damage at the cellular level and protecting DNA, lipids and proteins. Finally, green kiwi polyphenols have the ability to modulate the adaptive immune response, influencing the differentiation and activation of T lymphocytes, decreasing the activation of Th1 and Th17 cells, which are involved in the chronic inflammation of various autoimmune diseases. Preclinical studies provide evidence on the beneficial effects of polyphenols extracted from kiwifruit peel in autoimmune diseases; however, clinical studies in humans are needed to determine their efficacy, safety and possible therapeutic applications. The findings of this review contribute to elucidate the biochemical interactions of polyphenols extracted from green kiwifruit in autoimmune pathologies, highlighting the opportunities and limitations of their use as a natural strategy for the treatment of autoimmune diseases.