CRISPR-Cas nuclease-based genome editing aims to precisely modify the human genome. The introduced DNA double-strand breaks (DSBs) are typically repaired by non-homologous end-joining (NHEJ). It is well known that imperfect repair can lead to small insertions and deletions (indels) at the target site, and it has been speculated that large on-target aberrations are due to repeated cleavage of the target site by the programmable nuclease. Furthermore, DNA repair of multiple DSBs, e.g., a target site and an off-target site, may result in chromosomal translocations. We hypothesized that preventing repeated re-cleavage of the target site would reduce on-target aberrations as well as the frequency of translocations. To test this hypothesis, we targeted different loci in the human genome with a "double-hit strategy", i.e. we designed two CRISPR-Cas9 nucleases that targeted each locus (BCL11A, CD40L, CSF2) within 100 bp. To assess the extent and the frequency of chromosomal rearrangements, we used CAST-Seq and rhAmpSeq. Our data indicate that the use of two CRISPR-Cas9 nucleases to excise a ~80 bp DNA fragment reduced the frequency of large on-target deletions at e.g. the BCL11A locus by a factor of two and the average deletion size from 780 to 430 bp. Furthermore, the number of chromosomal translocation events between two target sites, e.g. CD40L and CSF2, was lowered 3-fold when each locus was hit twice instead of once. In conclusion, our study shows that large on-target aberrations and the frequency of chromosomal translocations can be mitigated by applying a CRISPR-Cas double-hit strategy.