Nanomaterials have emerged with a range of applications in medicine to enhance the drug delivery systems and to reach the specific target sites with reduced side effects. Nanomaterials with phytochemicals is one of the auspicious therapeutic approaches to treat metabolic diseases including insulin resistance. These nanomaterials target insulin resistance factors through various metabolites of liver including protein kinases (PK), which are catalysts synchronized through the process of phosphorylation, accessory domains, or allosteric ligand modulators. Among them, phosphoinositide 3-kinase (PI3K) is an important protein kinase involved in growth entity, precious cellular and metabolism such as cell proliferation, survival, glucose homeostasis, lipid transformation, and protein synthesis. Particularly, dysfunction of the PI3K/AKT sequence of life has been reported to cause insulin resistance. Biological agents (ligands) comprising growth regulating factors, mediators like hormones and cytokines, G-protein-coupled receptors (GPCR), receptor tyrosine kinases (RTKs), and renin-angiotensin system (RAS) activate PI3K. They reduce the formation of mainly VLDL1, subsequently inactivate glycogen synthase kinase-3ß (GSK-3ß) and activate glycogen synthase. Many research reports indicate that nanomaterials modified the PI3K inhibitors which enhance the consequent phosphorylation and activation for glucose homeostasis. This review provides an overview of the PI3K metabolism, impacts of nanomaterials and insulin resistance.