<p>Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are caused largely by protein fibril misfoldings, their aggregation, mitochondrial dysfunction and irregularity in cell signalling pathways. Due to the presence of the blood brain barrier and poor target specificity, the traditional therapeutics showed limited success. In recent times, with the progress in computational biology and artificial intelligence a structurally precise, highly stable de novo microproteins with tunable binding affinity have been designed to treat such deleterious diseases. These engineered small proteins through selective binding with the amyloid protein fibrils as well as by enhancing mitochondrial function and proteostasis prevent the onset and progression of neural disorders. This review highlights de novo design of microproteins, their mechanisms of action, challenges and future prospects in neurodegenerative pathologies. Collectively, de novo designed microproteins represent a promising candidate in curing of neural diseases.</p>