The neuropathological features of Alzheimer’s disease include amyloid plaques. Rapidly emerging evidence suggests that Piezo1, a mechanosensitive cation channel, plays a critical role in transforming ultrasound-related mechanical stimuli through its trimeric propeller-like structure, but the importance of Piezo1-mediated mechanotransduction in brain functions is less appreciated. However, apart from mechanical stimulation, Piezo1 channels are strongly modulated by voltage. We assume that Piezo1 may play a role in converting mechanical and electrical signals, which could induce the phagocytosis and degradation of Aβ, and the combined effect of mechanical and electrical stimulation is superior to single mechanical stimulation. Hence, we design a transcranial magneto-acoustic stimulation (TMAS) system, based on transcranial ultrasound stimulation (TUS) within a magnetic field that combines a magneto-acoustic coupling effect electric field and the mechanical force of ultrasound, and applied it to test the above hypothesis in 5xFAD mice. Behavioral tests, in vivo electrophysiological recordings, Golgi–Cox staining, enzyme-linked immunosorbent assay, immunofluorescence, immunohistochemistry, real-time quantitative PCR, Western blotting, RNA sequencing, and cerebral blood flow monitoring were used to assess whether TMAS can alleviate the symptoms of AD mouse model by activating Piezo1. TMAS treatment enhanced autophagy to promote the phagocytosis and degradation of β-amyloid through the activation of microglial Piezo1 and alleviated neuroinflammation, synaptic plasticity impairment, and neural oscillation abnormalities in 5xFAD mice, showing a stronger effect than ultrasound. However, inhibition of Piezo1 with an antagonist, GsMTx-4, prevented these beneficial effects of TMAS. This research indicates that Piezo1 can transform TMAS-related mechanical and electrical stimuli into biochemical signals and identifies that the favorable effects of TMAS on synaptic plasticity in 5xFAD mice are mediated by Piezo1.