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The DNA damage induced by five FDA-approved antiviral drugs was studied.Dye-based absorption and fluorescence spectroscopy, and MALDI-TOF mass spectrometry were used to quantify the DNA damage.Two drugs, ledipasvir and daclatasvir, consistently show evidence of drug-induced DNA damage.Fluorimetric studies of the rate of the drug-induced DNA damage show its dependence on the drug concentration.This work suggests a novel approach for the treatment of hepatitis B and C patients with hepatocellular carcinoma.Hepatocellular carcinoma is one of the most common malignant tumors in the world. Chronic hepatitis B and C infections are the most common etiologies of hepatocellular carcinoma worldwide. In this study, we explore the potential DNA damaging effect of some FDA-approved antiviral drugs which may be able to serve as anticancer agents for hepatocellular carcinoma, in order to better elucidate their mode of action. Five antiviral drugs were selected; ribavirin, sofosbuvir, tenofovir disoproxil fumerate, daclatasvir and ledipasvir. Several methods, including absorption spectroscopy, MALDI-TOF mass spectrometry and fluorimetric analysis using the EvaGreen (EG) intercalating dye, were used to probe the drug-induced DNA damage. Results show that only daclatasvir and ledipasvir induced DNA damage. Absorption spectroscopy showed hyperchromicity in the 260-nm DNA absorption band of DNA samples incubated with each drug, indicating disruption of the double-strand structure. Mass spectra for DNA samples incubated with each of the two drugs showed a disappearance of the DNA molecular ion peak with a concomitant appearance of peaks with smaller m/z, indicating DNA strand breaks. EG fluorescence was observed to decrease with increasing incubation time of daclatasvir and ledipasvir with DNA, indicating that the EG detaches from the DNA, likely due to DNA damage. All of these results are consistent with DNA damage, proposed as oxidative damage to both nucleobase and deoxyribose moieties of DNA as the mode of action for these two drugs. Moreover, these results are dependent on the antiviral drug concentration and show that DNA regions rich in guanine are affected more than other regions by these two drugs. Therefore, such antiviral drugs may present a promising therapeutic alternative to the currently used anticancer agents, especially for hepatitis B and C patients with hepatocellular carcinoma resistant to conventional treatment approaches.