Network hyperexcitability is a well-documented feature of Alzheimer’s disease (AD), although its reported clinical prevalence varies. Antidepressants are known to affect network hyperexcitability, and given their widespread use in AD, might contribute to these discrepancies. Therefore, in this study, we investigated whether chronic antidepressant treatment with fluoxetine influences network hyperexcitability in the Tg2576 AD mouse model. Mice underwent 13-days of EEG recording coupled with chronic fluoxetine treatment, delivered via intraperitoneal injections for five days and in drinking water for five additional days. Fluoxetine led to the expected changes in sleep structure. Epileptic seizures emerged by day 3 in Tg2576 mice, with nearly 50% exhibiting seizures by the end of the study. Almost 20% of the Tg2576 mice succumbed to fatal seizures. In contrast, only a few epileptic events, but no seizures, appeared in non-transgenic control animals by the end of the study. Our findings show that chronic fluoxetine treatment exacerbates epileptic activity in an AD mouse model, warranting further investigation into the safety of Selective Serotonin Reuptake Inhibitors (SSRIs) in AD patients.