Alzheimer’s disease is a neurodegenerative disorder with Amyloid-β plaques onset, synaptic damage, and cognitive decline. Aβ deposits cause pathological events including oxidative stress, mitochondrial dysfunction, and neuron death. In this study, APPswe/PSENΔ9 double transgenic mice model was used to imitate Alzheimer’s disease and the effect and possible mechanism of Andrographolide sulfonate were examined. Andrographolide sulfonate was given to the mice for 7 months before the onset of Aβ plaque. Spatial memory test showed that Andrographolide sulfonate treatment prevented cognitive decline. Aβ deposits were not affected while hippocampus and synapse damage was significantly alleviated. Mechanism studies showed that oxidative stress and mitochondrial swelling was reduced after Andrographolide sulfonate administration. These findings suggest that Andrographolide sulfonate, which has been applied in clinical medicine, might be a promising therapeutic agent for AD therapy via mitochondria protection.