Ischemic reperfusion injury (IRI) in the kidney is a common cause of acute-kidney-injury. Our aim is to compare the effects of Xanthenone /Irisin on alleviating inflammation, cell apoptosis and oxidative stress injury in kidney IRI via modulating the PI3K/Akt/eNOS and TLR4-NFkB pathways. 32 male rats were equally divided into groups: Control, IR, IR treated with (i.v) Xanthenone (10mg/kg), IR treated with (i.p) Irisin (100 µg/kg). Renal functions, blood pressure, renal tissue ACE2, Ang 1-7, inflammatory, oxidative stress and apoptotic markers were evaluated. Also, PI3K/AKT/eNOS and TLR-4 relative mRNA levels in renal tissue were assessed. Also, the protein concentration of pAKT, eNOS, histomorphological, and immunohistochemical analysis were done. In IR group, renal function tests, blood pressure, and apoptotic parameters were elevated. ACE2 and Ang (1-7) tissue levels, relative gene expression of PI3K/AKT/eNOS and TLR-4, the protein concentration of pAKT and eNOS, histomorphological and immunohistochemical analysis of NFkB in renal tissue were all distorted in IR group. However, Xanthenone and Irisin treatments improved renal function, inflammation, and oxidative stress through PI3K/AKT/eNOS and TLR-4/ NFĸB pathway. Moreover, Xanthenone acts through ACE2/Ang (1-7) pathway, while Irisin acts mainly through PI3K/AKT/eNOS and TLR4/NFkB pathway. This may increase the potential for combined Xanthenone and Irisin therapy during conditions of AKI.