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As the population ages, a high prevalence of multimorbidity will affect the way physicians need to think about drug interactions. With microglia's important involvement in the pathology and progression of Alzheimer's disease (AD), understanding whether systemically administered drugs intended for other affections could impact microglia function, already impacted by the presence of beta-amyloid, is important. The aim of this study was to evaluate morphological changes of microglia, using in vivo 2-photon laser scanning microscopy, in a murine model of AD under systemic administration of sodium or calcium ion channel blockers in order to establish potential effects that these drugs might have on microglia under neuro-inflammatory conditions. A total of 30 mice (age 14–16 weeks, weight 20–25 g) were used, with 25 APP randomly divided into three groups. The remaining animals were CX3CR1GFP/GFP male mice (n = 5) used as WT controls. After baseline behavior testing, all animals received daily intraperitoneal injections for 30 days according to the assigned group [WT (n = 5), Control (n = 5), Carbamazepine (n = 10), and Verapamil (n = 10)]. The results showed that the Verapamil treatment improved short-term memory and enhanced exploratory behavior in APP mice. The Carbamazepine treatment also improved short-term memory but did not elicit significant changes in anxiety-related behavior. Both Verapamil and Carbamazepine reduced the surveillance speed of microglia processes and changed microglia morphology in the cortex compared to the Control group. Due to their complex molecular machinery, microglia are potentially affected by drugs that do not target them specifically, and, as such, investigating these interactions could prove beneficial in our management of neurodegenerative pathologies. [ABSTRACT FROM AUTHOR]