Kidney disorders are among the most common diseases and there is a scarcity of effective treatments for chronic kidney disease. There has been a progressive improvement in specific flavonoids for protective effects against kidney diseases. Flavonoids inhibit the regulatory enzymes to control inflammation-related diseases. In the present study, a hybrid approach of molecular docking analyses and molecular dynamic simulation was followed by principal component analyses and a dynamics cross-correlation matrix. In the present study, the top-ranked five flavonoids were reported, and the maximum binding affinity was observed against AIM2. Molecular docking analyses revealed that Glu_186, Phe_187, Lys_245, Glu_248, Ile_263, and Asn_265 are potent residues against AIM2 for ligand–receptor interactions. Extensivein silicoanalyses suggested that procyanidin is a potential molecule against AIM2. Moreover, the site-directed mutagenesis for the reported interacting residues of AIM2 could be important for furtherin vitroanalyses. The observed novel results based on extensive computational analyses may be significant for potential drug design against renal disorders by targeting AIM2.