Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder that predominantly affects the elderly. Characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, AD leads to memory loss, cognitive decline, and severe behavioral changes. As the most common form of dementia, AD imposes a significant global health burden, highlighting the need for interventions that address underlying disease mechanisms rather than only symptomatic treatment. Glial cells, including microglia and astrocytes, play a crucial role in AD progression by mediating neuroinflammatory responses and modulating Aβ clearance and neuronal health. Dysfunction in these cells can exacerbate neuroinflammation and neuronal damage, making glial cells an important target for therapeutic intervention. This review synthesizes findings from in vivo and in vitro studies on melatonin's effects on glial cell dysfunction in AD, emphasizing the multi-mechanistic nature of its neuroprotective properties. Recent studies highlight melatonin's potential as a therapeutic agent that addresses AD-related mechanisms through its interactions with glial cells. Melatonin has demonstrated protective effects, including reducing oxidative stress, apoptosis, and inflammation, inhibiting Aβ fibrillogenesis, and modulating amyloid precursor proteins. Additionally, its influence on glial cell activity, through melatonin receptor pathways, suggests it can alleviate neuroinflammation, a key component of AD progression. The collective evidence points to melatonin's promise as a therapeutic tool with potential roles in both preventive and adjunctive treatments for AD. However, further research is necessary to establish its efficacy and safety in clinical settings.