Diabetes is a metabolic disorder that has notable impacts on human health. Since improving insulin sensitivity and metabolic homeostasis is important for the treatment of diabetes and its complications, there is a need to evaluate therapies that improve insulin resistance. The aim of the present review was to introduce the effects of the insulin receptor substrate (IRS)/PI3K/Akt pathway on insulin resistance by summarizing and evaluating all existing insulin signaling pathway studies as the entry point, and to integrate the processes and mechanisms through which drugs alleviate insulin resistance. Peer‑reviewed studies and reports on diabetes, insulin resistance and drug therapy were retrieved by searching websites such as PubMed (https://pubmed.ncbi.nlm.nih.gov/) and China National Knowledge Infrastructure (CNKI, https://www.cnki.net/), as well as by a manual search. The present review discusses the association between diabetes and the IRS/PI3K/Akt pathway, the treatment of diabetes by regulating this pathway to alleviate insulin resistance, the process and mechanism of combining drugs to alleviate insulin resistance, including natural compounds, Traditional Chinese Medicine and active ingredients, and the latest modern treatment methods. In conclusion, the present review summarizes the potential role of the IRS/PI3K/Akt pathway in the treatment of diabetes through its effect on insulin resistance and elucidates the therapeutic effects of drugs targeting this pathway.