Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder, which is mainly characterized by the presence of Lewy bodies in dopaminergic neurons of substantia nigra pars compacta (SNpc). Lewy bodies mainly consist of the misfolded α-synuclein, a cytosolic protein, whose accumulation and aggregation in neuronal cells is the primary underlying cause of neurotoxicity in PD. The E3 ubiquitin ligases mediate the clearance of misfolded proteins, including α-synuclein aggregates. The mutation or dysregulations of the E3 ubiquitin ligases result in the accumulation of the α-synuclein aggregates and related α-synucleinopathies-induced neurotoxicity, driving the progression of PD. This book chapter will explore the current understanding of the role of E3 ubiquitin ligases in the homeostatic mechanisms essential for neuronal function and survival and how their dysregulation contributes to the onset and progression of PD. We have provided an overview of molecular mechanisms involved in α-Synuclein misfolding and aggregation and the role of E3 ubiquitin ligases. Here we discuss different types of E3 ubiquitin ligases, their structural significance, systemic roles, signaling components, and their role in genetic, mechanical, and pathological changes in PD. Clearance of α-synuclein can be a core focus for PD-based therapeutics. Hence, we have also discussed the strategies with α-synuclein ubiquitination as primary targets against PD. E3 ubiquitin ligases and their roles in vital biological processes, especially protein clearance, make them promising and effective targets for therapeutic applications against PD.