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Abstract Objective Alzheimer's disease (AD) is often associated with neuropsychiatric symptoms, including agitation and aggressive behavior. These symptoms increase with disease severity, ranging from 10% in mild cognitive impairment to 50% in patients with moderate‐to‐severe AD, pose a great risk for self‐injury and injury to caregivers, result in high rates of institutionalization and great suffering for patients and families. Current pharmacological therapies have limited efficacy and a high potential for severe side effects. Thus, there is a growing need to develop novel therapeutics tailored to safely and effectively reduce agitation and aggressive behavior in AD. Here, we investigate for the first time the use of focused ultrasound combined with anesthetic‐loaded nanodroplets (nanoFUS) targeting the amygdala (key structure in the neurocircuitry of agitation) as a novel minimally invasive tool to modulate local neural activity and reduce agitation and aggressive behavior in the TgCRND8 AD transgenic mice. Methods Male and female animals were tested in the resident‐intruder (i.e., aggressive behavior) and open‐field tests (i.e., motor agitation) for baseline measures, followed by treatment with active‐ or sham‐nanoFUS. Behavioral testing was then repeated after treatment. Results Active‐nanoFUS neuromodulation reduced aggressive behavior and agitation in male mice, as compared to sham‐treated controls. Treatment with active‐nanoFUS increased the time male mice spent in social‐non‐aggressive behaviors. Interpretation Our results show that neuromodulation with active‐nanoFUS may be a potential therapeutic tool for the treatment of neuropsychiatric symptoms, with special focus on agitation and aggressive behaviors. Further studies are necessary to establish cellular, molecular and long‐term behavioral changes following treatment with nanoFUS.