The importance of epigenetic changes as a measurable endpoint in nanotoxicological studies is getting more and more appreciated. In the present work, we analyzed the epigenetic effects induced by citrate- and PEG-coated 20 nm silver nanoparticles (AgNPs) in a model consisting of 4T1 breast cancer tumors in mice. Animals were administered with AgNPs intragastrically (1 mg/kg b.w. daily—total dose 14 mg/kg b.w.) or intravenously (administration twice with 1 mg/kg b.w.—total dose 2 mg/kg b.w.). We observed a significant decrease in 5-methylcytosine (5-mC) level in tumors from mice treated with citrate-coated AgNPs regardless of the route of administration. For PEG-coated AgNPs, a significant decrease in DNA methylation was observed only after intravenous administration. Moreover, treatment of 4T1 tumor-bearing mice with AgNPs decreased histone H3 methylation in tumor tissue. This effect was the most pronounced for PEG-coated AgNPs administered intravenously. No changes in histone H3 Lys9 acetylation were observed. The decrease in methylation of DNA and histone H3 was accompanied by changes in expression of genes encoding chromatin-modifying enzymes (Setd4, Setdb1, Smyd3, Suv39h1, Suv420h1, Whsc1, Kdm1a, Kdm5b, Esco2, Hat1, Myst3, Hdac5, Dnmt1, Ube2b, and Usp22) and genes related to carcinogenesis (Akt1, Brca1, Brca2, Mlh1, Myb, Ccnd1, and Src). The significance of the observed changes and the mechanisms responsible for their development are unclear, and more research in this area is warranted. Nevertheless, the present work points to the epigenetic effects as an important level of interaction between nanomaterials and biological systems, which should always be taken into consideration during analysis of the biological activity of nanomaterials and development of nanopharmaceuticals.