Expanded CAG/CTG repeats cause at least 15 different neurodegenerative and neuromuscular diseases that all remain without an effective disease modifying treatment. Because the size of the repeat tract accounts for the majority of the variation in disease severity, contracting them presents an attractive therapeutic avenue. Here, we show that the CRISPR-Cas9 nickase targeted to the CAG/CTG repeat itself leads to efficient contractions in Huntington’s disease patient-derived neurons and astrocytes as well as in myotonic dystrophy type 1 patient-derived neurons. Using single-cell DNA sequencing and PCR-free whole genome sequencing, we found no off-target mutations in either neurons or astrocytes. Furthermore, we delivered the Cas9 nickase and sgRNA using adeno-associated virus stereotactically to a mouse model of Huntington’s disease and found contractions accumulating in over half of the infected cells over a period of 5 months. We also found that the Cas9 nickase was prone to silencing, further improving the safety of the approach. Our results provide the proof-of-concept for using the Cas9 nickase to contract the repeat tract safely in multiple diseases.