Ischemia and reperfusion injury (I/R) is a serious condition leading to organ failure, characterized by poor blood supply followed by rapid resuscitation of blood flow and reoxygenation. Renal failure caused by renal ischemia has high mortality and morbidity. This study aimed to explore the potential role of Semaglutide as a novel and effective therapeutic strategy for acute renal failure. Additionally, we aimed to assess the possible protective effect of Semaglutide on kidney I/R injury in mice through modulation of the inflammatory and oxidative pathways via phosphatidylinositol 3-kinase/adenosine triphosphate (PI3K/AKT) activation. We employed twenty-eight albino mice to induce the I/R injury model by clamping the renal artery for 30 min followed by a period of reperfusion for 2 hours. The control group was exposed to I/R injury, while the Semaglutide-treated group was pretreated with the drug 12 hours before induction of ischemia at a dose of 100 nmol/L/kg via the intraperitoneal route (i.p). In addition, the DMSO-treated group was subjected to similar conditions to the Semaglutide-treated group. At the end of the experiments, kidneys and blood samples were collected for investigation. Semaglutide could act as a protective agent against acute kidney injury by reducing inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and its cognate receptor, TNF-α R, interleukine-6 (IL-6). Furthermore, Semaglutide reduced F8 isoprostane levels, increased PI3K and AKT levels in renal tissues, and mitigated renal damage. Semaglutide had renoprotective effects via modulation of the inflammatory response and oxidative pathway by targeting the PI3K/AKT signaling pathway.