Protein misfolding is the central pathological event that sparks neurodegenerative diseases (NDDs), including Alzheimer’s, Parkinson’s, and Huntington’s disease. Through the formation of these protein aggregates, cells become dysfunctional and die, severely impairing the communication within the neural network, resulting in a progressive lowering of cognitive and motor functions. Considering the great quality of life impact on patients, the development of effective strategies to block such neurodegenerative processes has recently become the focal point of much research work. This chapter gives an elaborate view of protein misfolding and cell death consequences, along with multiple strategies employed against those effects in a therapeutic approach. Innovative approaches, including neuroprotective compounds from natural products, as well as cutting-edge molecular techniques, such as targeted protein degradation, are also addressed. These kinds of approaches not only inhibit neuron damage but also repair and reconstitute normal cellular function.