Expansion of CAG and CTG (CWG) triplet repeats is causal in a number of inherited neurological diseases. The CWG triplet repeat diseases can be broadly classified into coding and non-coding types based on their location in the genome, such as Huntington’s disease (HD) by expanded CAG repeat in a coding region and myotonic dystrophy type-1 (DM1) by expanded CTG repeat in a 3’-untranslated region. The CWG repeat diseases are thought to induce complex pathogenic mechanisms through expanded CWG repeat-derived RNAs and polypeptides. Here we show a CWG repeat DNA targeting compound, cyclic Pyrrole-Imidazole Polyamide (CWG-cPIP) suppresses the pathogenesis of coding and non-coding CWG repeat diseases. CWG-cPIP binds to hairpin form of the mismatched CWG DNA, interfering with transcriptional elongation of RNA polymerase in a repeat length-dependent manner. CWG-cPIP inhibits pathogenic mRNA transcripts from expanded CWG repeat, result in reduction of CUG RNA foci and polyglutamine accumulations in DM1 and HD patient cells and mouse models, respectively. Treatment with CWG-cPIP also ameliorates learning and memory deficits and synaptic dysfunction in DM1 and HD mouse models with less off-target effects. Taken together, we present a novel candidate compound that targets expanded CWG repeat DNA independent of genomic location, demonstrating the concept of reducing the levels of pathogenic RNAs and proteins.