Alzheimer’s disease (AD) is an age-related neurodegenerative disease with multiple predisposing factors and complicated pathogenesis. Aβ peptide is one of the most important pathogenic factors in the etiology of AD. Accumulating evidence indicates that the imbalance of Aβ production and Aβ clearance in the brain of AD patients leads to Aβ deposition and neurotoxic Aβ oligomer formation. Melatonin shows a potent neuroprotective effect and can prevent or slow down the progression of AD, supporting the view that melatonin is a potential therapeutic molecule for AD. Melatonin modulates the regulatory network of secretase expression and affects the function of secretase, thereby inhibiting amyloidogenic APP processing and Aβ production. Additionally, melatonin ameliorates Aβ-induced neurotoxicity and probably promotes Aβ clearance through glymphatic-lymphatic drainage, BBB transportation and degradation pathways. In this review, we summarize and discuss the role of melatonin against Aβ-dependent AD pathogenesis. We explore the potential cellular and molecular mechanisms of melatonin on Aβ production and assembly, Aβ clearance, Aβ neurotoxicity and circadian cycle disruption. We summarize multiple clinical trials of melatonin treatment in AD patients, showing that melatonin has a promising effect on improving sleep quality and cognitive function. This review aims to stimulate further research on melatonin as a potential therapeutic agent for AD.