Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of upper and lower motor neurons, accompanied by neuroinflammation and TDP-43 proteinopathy, leading to muscle atrophy and paralysis. Ataxin-2 has been identified as a key modulator of TDP-43 toxicity, and its reduction has been shown to alleviate neurodegeneration and improve survival in ALS models, making it a promising therapeutic target for modifying disease progression. In this study, we developed lipid-modified degron peptides targeting Ataxin-2 for proteasomal degradation. We performed high-density peptide screening followed by 3D structure modeling to identify the optimal Ataxin-2 binding sequence. In vitro experiments demonstrated that degron peptides induce dose- and time-dependent degradation of Ataxin-2 in primary cultured neurons. To enhance peptide stability and tissue penetration, we employed lipidation strategies incorporating C20 and C16 fatty acid modifications, which significantly improved degron peptide efficacy in vivo. In TAR4/4 ALS mice, lipid-modified Ataxin-2-targeting degron peptides ameliorated motor neuron loss, improved motor function, and prolonged survival. Interestingly, despite these therapeutic benefits, TDP-43 aggregation was not significantly reduced, suggesting that Ataxin-2 depletion exerts effects through mechanisms beyond direct TDP-43 modulation. However, our findings showed a significant reduction in neuroinflammation in TAR4/4 ALS mice following peptide treatment. These results not only establish lipid-modified degron peptides as a viable therapeutic strategy for ALS but also provide a broader framework for targeting disease-relevant proteins implicated in neurodegeneration. This study paves the way for developing precision-targeted therapeutics with enhanced stability, bioavailability, and efficacy for ALS and other neurodegenerative diseases.