Influenza A virus (IAV) exhibits a high mutation frequency. Mutations in primary viral targets such as hemagglutinin, neuraminidase, and the proton channel M2 have afforded IAV with substantial drug resistance to previously effective drugs such as oseltamivir and amantadine (AMT) along with their analogs. One of the main drug-resistant alterations in the M2 protein that has become ubiquitous is the mutation S31N. Divalent copper has previously been suggested to have anti-IAV properties using in vitro assays involving Xenopus oocytes and SSNMR. In this work, the EC50 of AMT, two AMT analogs, CuCl2 · 2H2O, and four previously published Cu2+ complexes were tested for antiviral activity against the California/07/2009 (H1N1) IAV strain containing the S31N M2 protein in viral mini-plaque assays. AMT, CuCl2 · 2H2O, and two previously published divalent copper complexes were tested for M2 proton-transport blocking efficacy in liposomes using truncated M2 (22-62, S31N). Two novel divalent copper species, NAG101 and NAG107, both derived from AMT analogs were developed and tested for both antiviral activity and M2 blocking efficacy. Cell integrity was maintained at concentrations up to 1 mM (48 hours of exposure) with all compounds except Cu(II) 3. In the viral mini-plaque assay the novel divalent copper complexes NAG101 (EC50 25.7 +/-7.7 µM) and NAG107 (EC50 2.91 +/- 0.29 µM) were 2.5-fold and 21-fold better than AMT (EC50 64.3 +/- 9.3 µM) respectively. In the liposome assay NAG101 (EC50 18.9 +/- 1.5 µM) and NAG107 (EC50 4.5 +/- 0.6 µM) were 2.5-fold and 11-fold better than AMT (EC50 49.3 +/- 2.9 µM respectively. In the viral mini-plaque assay, CuCl2 · 2H2O (EC50 57.2 +/- 10.1 µM) was comparably effective to AMT, but was more than ten times more effective in the liposome assay targeting S31N M2 with an EC50 6.1 +/- 0.8 µM. Divalent copper species possess anti-IAV activity against the ubiquitous S31N M2-containing viral strain California/07/2009 (H1N1) and may prove to be effective against other IAV strains by blocking M2.