In Alzheimer's disease pathology, inhibitors of nuclear factor kappa-β kinase subunit β (IKKB) and Tumor necrosis factor receptor 1 (TNFR1) signaling are linked to neuroinflammation-mediated cognitive decline. We explored the role of a phosphodiesterase 5 inhibitor (PDE5I) with dual antagonistic action on IKKB and TNFR1 to inhibit nuclear factor kappa B (NF-kB) and curb neuroinflammation. In the in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The top compound with dual antagonistic action on IKKB and TNFR1 was selected based on bonding and non-bonding interactions. Further, induced fit docking (IFD), molecular mechanics-generalized Born and surface area (MMGBSA), and molecular dynamic studies were carried out and evaluated. Lipopolysaccharide (LPS) administration caused a neuroinflammation-mediated cognitive decline in mice. Two doses of avanafil were administered for 28 days while LPS was administered for 10 days. Morris water maze (MWM) along with the passive avoidance test (PAT) were carried out. Concurrently brain levels of inflammatory markers, oxidative parameters, amyloid beta (Aβ), IKKB and NF-kB levels were estimated. Avanafil produced good IKKB and TNFR1 binding ability. It interacted with crucial inhibitory amino acids of IKKB and TNFR1. MD analysis predicted good stability of avanafil with TNFR1 and IKKB. Avanafil 6 mg/kg could significantly improve performance in MWM, PAT and oxidative parameters and reduce Aβ levels and inflammatory markers. As compared to avanafil 3 mg/kg, 6 mg/kg dose was found to exert better efficacy against elevated Aβ , neuroinflammatory cytokines and oxidative markers while improving behavioural parameters.Communicated by Ramaswamy H. Sarma.