Ischemic stroke (IS) is an acute cerebrovascular disease caused by sudden arterial occlusion, which is characterized by a high morbidity, mortality, and disability rate. It is one of the most important causes of nervous system morbidity and mortality in the world. In recent years, the search for new medicine for the treatment of IS has become an attractive research focus. Due to the extremely limited time window of traditional medicine treatment, some side effects may occur, and accompanied by the occurrence of adverse reactions, the frequency of exploration with natural medicine is significantly increased. Phosphatidylinositol-3-kinase/Protein kinase B (PI3K/Akt) signaling pathway is a classical pathway for cell metabolism, growth, apoptosis, and other physiological activities. There is considerable research on medicine that treats various diseases through this pathway. This review focuses on how natural medicines (including herbs and insects) regulate important pathophysiological processes such as inflammation, oxidative stress, apoptosis, and autophagy through the PI3K/Akt signaling pathway, and the role it plays in improving IS. We found that many kinds of herbal medicine and insect medicine can alleviate the damage caused by IS through the PI3K/Akt signaling pathway. Moreover, the prescription after their combination can also achieve certain results. Therefore, this review provides a new candidate category for medicine development in the treatment of IS.