Alzheimer’s disease (AD), the leading cause of dementia worldwide, presents a critical and growing health challenge due to limited therapeutic options and an incompletely understood pathogenesis. Neuronal health is largely dependent on protein homeostasis, a balance sustained primarily by the ubiquitin-proteasome system (UPS) and autophagy, the two main protein degradation systems. E3 ubiquitin ligases play a central role in these systems, directing the tagging and degradation of specific proteins. A growing body of evidence indicates that dysregulation of E3 ligases plays a significant role in the progression of AD. Their impairment promotes the accumulation of pathogenic proteins, such as amyloid-beta (Aβ) and tau, exacerbating endoplasmic reticulum (ER) stress. While central to proteostasis, E3 ligases are also crucial for other interconnected cellular processes involved in AD, such as synaptic integrity, mitochondrial function, neuroinflammatory responses, cell cycle control, DNA repair, calcium homeostasis, and cell survival pathways. This review explores the multifaceted roles of E3 ubiquitin ligases in Alzheimer’s disease pathology, highlighting their influence on cellular mechanisms that drive disease progression and advocating for further research into targeted therapeutic strategies that may alter the disease course.