Acute kidney injury secondary to renal ischemia-reperfusion is associated with high morbidity and mortality rates. Understanding the pathogenesis of this condition is essential to explore effective treatment. Traditional approach for treating diseases i.e., “one-drug/one-target/one-disease” faces an efficacy problem and diminished translational success. A shift towards multi-target therapies would be the alternative for bridging this translational gap. This can be achieved through network pharmacology. Network pharmacology subdivides complex diseases based on their causal mechanisms into disease networks or modules and suggests targeting such modules by low-dose drug combinations and thus improves safety and efficacy. This study was intended to identify AKI disease module with potential drug targets that was performed utilizing Disease Module Detection algorithm using NOXs as seeds. We then assessed the protective effect of a multi-target network pharmacology targeting the identified module in a rat model of RIRI. Rats were divided into five groups; sham, RIRI, and RIRI treated with setanaxib (NOX inhibitor, 10 mg/kg), etanercept (TNF-α inhibitor, 10 mg/kg), and setanaxib and etanercept (5 mg/kg each). Kidney functions, histopathological changes and oxidative stress markers (MDA and reduced GSH) were assessed. Immunohistochemistry of inflammatory (TNF-α and NF- κB) apoptotic (cCasp-3, Bax/Bcl 2), fibrotic (α-SMA) and proteolysis (MMP-9) markers was performed. Moreover, this study examined the acute toxicity of Symphyotrichum Squamatum alcoholic root extract and its renoprotective effects against RIRI in rats. In addition, LC-MS/MS was used to characterize the chemical composition in SSRE. Animals received a single oral dose of 5000 mg/kg of either SSRE or vehicle. Their body weight, organ weight, blood chemistry, and general health were closely monitored for 28 days. Next, network pharmacology was utilized to explore potential interactions between key components of SSRE and proteins associated with RIRI pathogenesis. Finally, an in vivo AKI model was established in rats to assess the renoprotective effect of SSRE. Animals were divided into four groups: sham, AKI, and AKI treated with SSRE (at doses of 500 or 1000 mg/kg). Following AKI induction, kidney function and structure were evaluated in all groups.