Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are likely to be the leading cause of disability in the upcoming decades. The pathological development in these diseases is driven by a triad of protein aggregation, oxidative stress, and autophagic dysfunction. This chapter examines how these factors, accelerate neuronal degeneration. Misfolded proteins like amyloid-β, tau, and α-synuclein directly impair autophagic clearance. Reactive oxygen species inactivate redox-sensitive autophagy regulators and proteostasis machinery. Altogether, these disruptions create toxic feedback loops that trigger neuroinflammation. An ideal therapeutic strategy should be focused on targeting multiple pathways of the triad rather than a single target. Gene editing, redox-modulating prodrugs, and biomarker-guided timing are some of the promising tools which takes into account the multifaceted pathological aspects of neurodegenerative diseases. This chapter discuss the role and inter-relation of aforementioned pathological mechanisms and multi-target therapeutic approach to combat neurodegeneration in an effective manner.