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The ability of antiviral polyamides (AVP) to act upon polyomaviruses (PyV) was evaluated. Initial studies found that a single treatment of AVP protected SV40-infected BSC-1 cells from cytopathic effect (CPE) for as long as 11 days p.i. AVP substantially suppressed SV40 genome copy numbers over the duration of the experiment. Immunofluorescence analysis of ataxia-telangiectasia mutated (ATM) activation and large T antigen (LTag) expression clearly demonstrated that AVP treatment at day 1 p.i. delayed the onset of productive SV40 replication by approximately 3 days, and substantially limited the infection relative to vehicle-treated controls. AVP dose-response experiments recorded IC50s in the low nM range that were similar to IC50s previously reported for HPV16. The ability of AVPs to act on BKPyV was next examined. Again, IC50s in the low nM range were obtained with the exception of an AVP (PA1) that gave an IC50 of 437 nM against the BKPyV Dunlop strain. The Mre11 inhibitor Mirin substantially reduced the AVP IC50 against SV40 demonstrating that Mre11 protects PyV genomes from AVP action as previously shown for HPV. Together these experiments show that AVPs are potent antiviral agents for PyV that act via a mechanism with similarities to that found for HPV. The results demonstrate that AVPs are useful tools for controlling and studying PyV biology. The potential use of these agents against BKPyV and other PyV pathogens also has clinical implications.The potent activity of antiviral polyamides (AVPs) against SV40 and BK Polyomaviruses is reported.AVPs show similarities in mechanism of action between polyomaviruses and papillomaviruses.A single AVP treatment has long lasting antiviral effects against polyomaviruses.