Migraine is a disabling chronic condition of the central nervous system (CNS) with accelerated prevalence in females. Emerging studies demonstrated that females with a history of migraine have a 37 % higher risk of developing Alzheimer’s disease (AD) compared to same-age males with a history of migraine. To date, it remains unclear how to address sex-associated migraine disorder in patients with AD due to our limited knowledge of the molecular crosstalk behind these two CNS disorders. There are no available animal models that recapitulate both migraine pain and AD phenotypes. Since nitroglycerin (NTG) is widely used in clinics and in experimental wild-type rodent models to monitor migraine symptoms, we aimed to evaluate whether NTG accelerates migraine pain and affects AD hallmarks. Our group and previous reports have shown that the AD-like triple transgenic (3x-Tg) mice demonstrate behavioral changes and pathogenic amyloidogenesis in response to chronic inflammation. Therefore, we treated 3x-Tg mice every other day with ten intraperitoneal injections of NTG or saline. In response to NTG, female 3xTg mice demonstrated accelerated pain responses and diminished cognitive performance during a spatial learning and memory task compared to males and saline exposed groups. We also observed accelerated AD-associated amyloidogenesis in NTG-exposed females compared to the saline group. No sex differences between NTG-treated groups were detected relative to pain threshold, behavioral, and amyloidogenesis changes. Collectively, this novel migraine model induced in AD 3x-Tg mice allowed us to monitor the effect of NTG on the pain threshold, behavioral changes, and pathogenic amyloidogenesis in males and females.