Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which microglia-mediated neuroinflammation contributes to disease progression. Icariin (ICA), a major bioactive flavonoid from Epimedium, has neuroprotective activity, but how it regulates mitochondrial quality control and inflammatory injury in microglia remains unclear. In the present study, APP/PS1 transgenic mice and Aβ_1-42-stimulated BV-2 microglia were used to examine the effects of ICA on mitophagy, mitochondrial stress, NLRP3/GSDMD-related pyroptotic changes, and neuroinflammation. Behavioral testing, histological analysis, transcriptomic profiling, immunofluorescence, Western blotting, ELISA, molecular docking, molecular dynamics simulation, cellular thermal shift assay, Mdivi-1 co-treatment, and siRNA-mediated Pink1 knockdown were performed. ICA improved cognitive deficits in APP/PS1 mice and reduced microglial inflammatory activation. Transcriptomic and experimental analyses showed that ICA enhanced mitophagy-related responses, restored mitochondrial membrane potential, and reduced excessive mitochondrial reactive oxygen species accumulation. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay supported potential engagement of ICA with PINK1. ICA also reduced NLRP3 inflammasome-associated inflammatory injury, GSDMD-related pyroptotic changes, and IL-1β and IL-18 release. In APP/PS1 mice, Mdivi-1 co-treatment weakened the anti-inflammatory effects of ICA. In Aβ_1-42-stimulated BV-2 microglia, Pink1 knockdown reduced ICA-induced LC3/TOM20 colocalization and partially reversed the inhibitory effects of ICA on NLRP3 inflammasome-associated inflammatory markers. Overall, ICA enhances PINK1-associated mitophagy, alleviates mitochondrial stress, and attenuates NLRP3/GSDMD-related microglial pyroptotic injury in AD-related models. These findings suggest that PINK1-associated mitochondrial quality control contributes to the neuroprotective effects of ICA.