The influence of the surface chemistry of silver nanoparticles (AgNPs) on p53 mediated cell death was evaluated using human dermal fibroblast (HDF) and lung cancer (A549) cells. The citrate reduced AgNPs (C-AgNPs) were modified with either lactose (L-AgNPs) or a 12-base long oligonucleotide (O-AgNPs). Both unmodified and modified AgNPs showed increased concentration and time dependent cytotoxicity and genotoxicity causing an increased p53 up-regulation within 6 h and led to apoptotic or necrotic cell deaths. The C-AgNPs induced more cytotoxicity and cellular DNA damage than the surface modified AgNPs. Modifying the C-AgNPs with lactose or the oligonucleotide reduced both necrotic and apoptotic cell deaths in the HDF cells. The C-AgNPs caused an insignificant necrosis in A549 cells whereas the modified AgNPs caused necrosis and apoptosis in both cell types. Compared to the O-AgNPs, the L-AgNPs triggered more cellular DNA damage, which led to up-regulation of p53 gene inducing apoptosis in A549 cells compared to HDF cells. This suggests that the different surface chemistries of the AgNPs cause different cellular responses that may be important not only for their use in medicine but also for reducing their toxicity.