Abstract: Neurological disorders are still one of the major causes of death, and the vast need to find efficacious therapy is nowadays an essential goal of the scientific community. For Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), spinal cord injury, and intracerebral hemorrhage, current pharmacological treatments are solely symptomatic, so there is a need to identify agents that can slow or stop neurodegeneration. Neurodegenerative diseases are caused by interactions between genetic, epigenetic, and environmental factors with consequent dysfunction of multiple cellular and molecular pathways. The multifactorial nature of the disorders could explain the modest results obtained by the treatments proposed so far. Moreover, the biochemical complexity of the pathological mechanisms highlights the need for multitarget therapies acting synergistically on different aspects of the diseases. Niclosamide, marketed as Yomesan for human use in 1962, is a Food and Drug Administration (FDA)-approved anti-helminthic drug used for over 50 years with considerable safety (Chen et al., 2018), and it is included in the World Health Organization’s list of essential medicines. Niclosamide is a member of the salicylanilide class of pharmacologic agents with an aryl β-hydroxy-carbonyl pharmacophore motif, usually present in many biological natural products. The pharmacophore motif confers to this small molecule its pleiotropic activities and the potential to interact with multiple biological targets. Its first documented action is to translocate protons across the mitochondrial membrane, resulting in mild mitochondrial uncoupling. This action is sufficient to kill tapeworms in the gastrointestinal tract but is generally well tolerated by human cells. In addition, niclosamide modulates Wnt/β-catenin, signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), nuclear factor-kappa B (NF-κB), transmembrane protein 16 (TMEM16), and Notch signaling pathways (Chen et al., 2018). Since these molecules drive the transcription of multiple genes, it is possible that the broad biological activity displayed by the compound is the result of direct or indirect effects on these signaling pathways. Thanks to its pleiotropic actions, in recent years, niclosamide has been repurposed for several diseases. Preclinical validation proved that niclosamide has efficacy against solid cancers, rheumatoid arthritis, and fibrotic conditions, and it is currently in phase II–III clinical trial for metastatic colorectal cancer, prostate cancer, and coronavirus disease 2019 (COVID-19; Singh et al., 2022).