A case study, detailing the effect of different DNA strands on a NIR-emitting DNA-stabilized silver nanocluster (DNA-AgNC), is reported. The presence of single-stranded DNA oligomers was found to adversely affect the chemical stability of (DNA)2[Ag16Cl2]8+ with distinct degrees of destruction depending on the DNA sequence. To increase the chemical stability of the DNA-AgNC, we implemented two protection strategies. First, hybridization of the bare DNA strands with the corresponding complementary sequences dramatically reduced the destruction of (DNA)2[Ag16Cl2]8+, as demonstrated by the decreased drops in both the absorption and emission spectra. Secondly, passivation of the bare DNA oligomers with silver cations left (DNA)2[Ag16Cl2]8+ intact. Our investigation can thus provide an easy-to-implement approach to discover DNA sequences that are intrinsically less reactive towards preformed DNA-AgNCs, and give an idea on how to protect DNA-AgNCs from bare DNA strands.