Rare earth elements have been shown to trigger the B-to-Z DNA transition in diverse self-assembled branched DNA architectures. Herein, we investigated the influence of cerium chloride on the conformational changes of DNA sequences containing repeated cytosine-guanine (CG) 6−12 or guanine-cytosine (GC) 6−12 sequences. The CD results show that (CG) 6−12 repeats were susceptible to the formation of Z-DNA at low concentrations of CeCl 3 . On the other hand, (GC) 6−12 is unable to undergo B-Z DNA transition and instead exhibits condensation with a similar amount of CeCl 3 . The CD signature was found to be different and unique in both alternate repeats during the interaction with CeCl 3 . The sequence-specific effects on the B-Z transition are based on the order of nucleotides in DNA. With the addition of EDTA, the Z-form of DNA is reverted to the native B-form. Further, we have reported the positive zeta potential of CeCl 3 -induced Z-DNA in contrast to the negative zeta potential of B-DNA. The differential zeta-potential value during the B-Z transition is complementary to the conformational changes of DNA. The molecular simulation study also supports the sequence-specific conformational change between the B-and Z-forms of DNA molecules. This newly described reversible topological and sequence-dependent transition is crucial for understanding the structural and biological roles of Z-DNA in response to CeCl 3 .