Elongated polyglutamine stretch in mutant huntingtin (mhtt) correlates well with the pathology of Huntington's disease (HD). Inhibition of aggregation of mhtt is a promising strategy to arrest disease progression. In this work, specific, high-affinity RNA aptamers were selected against monomeric mhtt (51Q-htt). Some of them inhibited its aggregation in vitro by stabilizing the monomer. They also recognized 103Q-htt but not 20Q-htt (nonpathogenic length). Inhibition of aggregation corresponded with reduced leakage of a fluorescent probe from liposomes and diminished oxidative stress in RBCs. The presence of aptamers was able to rescue the sequestration of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by aggregated mhtt. Some of the aptamers were able to enhance the partitioning of mhtt in the soluble fraction in a yeast model of HD. They were also able to rescue endocytotic defect due to aggregation of mhtt. The beneficial effect of a combination of aptamers was enhanced with improvement in cell survival. Since HD is a monogenic autosomal dominant disorder, aptamers may be developed as a viable strategy to slow down the progress of the disease. Since they are nonimmunogenic and nontoxic, aptamers may emerge as strong candidates to reduce protein-protein interaction and hence protein aggregation in protein misfolding disorders in general.