Andes virus (ANDV) is a highly pathogenic New World hantavirus found in Chile and Argentina that causes Hantavirus Pulmonary Syndrome (HPS). A significantly high case fatality rate, the potential for human-to-human transmission, and the lack of licensed vaccines or effective treatments for the disease suggest an urgent need for the development of such measures. Many vaccine platforms have been recently described using reverse genetics systems to generate attenuated virus strains, as well as recombinant viruses expressing foreign proteins. This study attempted to generate and characterize vaccines based on an ANDV infectious clone system, as well as a recombinant vesicular stomatitis virus (VSV) vector expressing the ANDV glycoprotein precursor (VSVΔG/ANDVGPC), to test their efficacy in the only lethal disease animal model of HPS. Although an ANDV infectious clone system was not successfully established, precluding its use as a possible vaccine candidate, the first New World hantavirus minigenome system was described. In addition, Syrian hamsters immunized with a single dose of the recombinant VSVΔG/ANDVGPC vaccine were fully protected against disease when challenged at 28, 14, 7, or 3 days post-immunization with a lethal dose of ANDV; however, the mechanism of protection seems to differ, depending on the time point of immunization. At 28 days post-immunization, a lack of detectable ANDV RNA in tissue samples as well as a lack of seroconversion against the ANDV nucleoprotein (N) in nearly all hamsters suggested mostly sterile immunity. The vaccine was able to generate high levels of neutralizing anti-ANDV GN/GC antibodies that seem to play a role as a mechanism of vaccine protection. Administration of the vaccine at 7 and 3 days before challenge also resulted in full protection, but the lack of a neutralizing humoral immune response and the up-regulation of hamster cytokines involved in innate pathways suggested a possible role of innate responses in protection. The role of innate immunity was supported by the fact that administration of the vaccine 24 hours post-challenge was successful in protecting 90% of hamsters. Overall, the data suggests the potential for the use of the VSV platform as a fast-acting and effective prophylaxis/post-exposure treatment against lethal hantavirus infections.