Drugs belonging to the non-steroidal anti-inflammatory drug group (NSAID) are not only used as anti-inflammatory and analgesic agents, but also exhibit chemopreventive and chemosuppressive effects on various cancer cell lines. They exert their anticancer effects by inhibiting both at the protein level and/or at the transcription level. Cu(II) complexes of these NSAIDs show better anti-cancer effects than the bare drugs. Considering the above aspects, it is of interest to see if Cu(II) complexes of these drugs can exert their effects directly at the DNA level. In this study, we have used UV-Vis spectroscopy to characterize the complexation between Cu(II) and two NSAIDs belonging to the oxicam group viz. piroxicam and meloxicam, both of which exhibit anticancer properties. For the first time, this study shows that, Cu(II)-NSAID complexes can directly bind with the DNA backbone, and the binding constants and the stoichiometry or the binding site sizes have been determined. Thermodynamic parameters from van't Hoff plots showed that the interaction of these Cu(II)-NSAID complexes with ctDNA is an entropically driven phenomenon. Circular dichroism (CD) spectroscopy showed that the binding of these Cu(II)-NSAIDs with ctDNA result in DNA backbone distortions which is similar for both Cu(II)-piroxicam and Cu(II)-meloxicam complexes. Competitive binding with a standard intercalator like ethidium bromide (EtBr) followed by CD as well as fluorescence measurements indicate that the Cu(II)-NSAID complexes could intercalate in the DNA.