Agitation represents one of the most debilitating neuropsychiatric dimensions of Alzheimer’s disease (AD), imposing a profound burden on patients’ quality of life and escalating caregiver burnout. While brexpiprazole has emerged as a frontline pharmacological candidate for managing these symptoms, a definitive consensus on its clinical utility has remained elusive. To address this, a comprehensive systematic review and meta-analysis were conducted, synthesizing data from four high-quality randomized controlled trials encompassing 1,413 participants. The analysis revealed that brexpiprazole yields a statistically significant reduction in agitation severity, as evidenced by a mean difference (MD) of −3.89 in Cohen–Mansfield Agitation Inventory scores (95% CI: −5.87 to −1.90; p = 0.0001). This primary finding is bolstered by moderate-certainty evidence and complemented by a significant, albeit modest, improvement in Clinical Global Impressions-Severity ratings (MD: −0.29; p = 0.002). Notably, the impact on the Neuropsychiatric Inventory-Nursing Home scores did not reach statistical significance, suggesting that the drug’s efficacy may be more pronounced in specific behavioral domains than in global neuropsychiatric health. Safety remains a critical consideration; the data indicate a heightened risk of treatment-emergent adverse events (risk ratio: 1.12; p = 0.04), supported by high-certainty evidence. Despite this risk, discontinuation rates were not significantly different from placebo, suggesting that the side effect profile is generally manageable. Ultimately, while brexpiprazole demonstrates clear therapeutic benefits for AD-related agitation, clinicians must prioritize vigilant monitoring and individualized risk-benefit assessments to mitigate potential adverse outcomes. Further long-term longitudinal research is warranted to validate these findings over extended durations.