Huntington’s disease (HD) is a neurodegenerative disorder characterized by several motor, cognitive and neuropsychiatric symptoms. HD is a progressive neurodegenerative disorder characterized by a triad of debilitating symptoms: motor dysfunction, cognitive decline, and neuropsychiatric disturbances. The disease primarily manifests in mid-adulthood but can occur earlier or later depending on genetic and environmental factors. Its clinical presentation is dominated by motor symptoms, including chorea, dystonia, bradykinesia, and impaired coordination. Cognitive symptoms range from difficulties in executive functions, such as planning and decision-making, to profound dementia in advanced stages. Neuropsychiatric symptoms include depression, anxiety, irritability, apathy, and, in some cases, psychosis, contributing significantly to the disease’s burden on patients and caregivers. The etiology of HD strongly relates to huntingtin (Htt) gene mutation, which leads to the production of an abnormal huntingtin protein that exerts neurotoxic effects on striatal medium spiny neurons and other neuronal populations. HD pathology is related to mitochondrial dysfunction, excitotoxicity, oxidative stress, glial reactivity and nuclear impairment, among other phenomena. Currently there is no available treatment that can delay or stop neurodegeneration. The ubiquitin-proteasome system (UPS) is the major proteolytic pathway in eukaryotes, maintaining proteostasis by selectively degrading misfolded, damaged, or unnecessary proteins. E3-ubiquitin ligase enzymes are proteins with a pivotal role in UPS-dependent protein degradation. At the heart of this system are the E3 ubiquitin ligases, enzymes that confer substrate specificity by tagging target proteins with ubiquitin molecules. This ubiquitination marks proteins for degradation by the proteasome, a process crucial for cellular homeostasis. In HD, the UPS is dysfunctional, contributing to the accumulation of mutant huntingtin and other misfolded proteins. Mutant huntingtin itself interferes with proteasome activity, creating a vicious cycle of impaired protein degradation and increased aggregate formation. Recent studies have highlighted the role of specific E3 ubiquitin ligases in HD pathogenesis, revealing their dual potential as contributors to disease mechanisms and as therapeutic targets. Here, the role of E3 ligases in the pathogenesis of HD will be discussed, highlighting their potential use as therapeutic targets for this currently incurable disease.