PRRSV is one of the most important viruses in the global swine industry and is often controlled by the use of modified live virus (MLV) vaccines. This study assessed the impact of a PRRSV-1 MLV vaccine applied to 1-day-old piglets challenged on day 28 of life with a PRRSV-1 field isolate (AUT15-33). Twenty-one piglets were vaccinated within 24 h of birth (T02), whereas 20 piglets were left unvaccinated (T01). Necropsy was performed two weeks post-challenge. Comparing the two groups, T02 piglets showed significantly higher (p = 0.017) average daily weight gain. In addition, significantly lower (p < 0.0001) PRRSV RNA loads were measured in serum of T02 piglets at all investigated time points. All T01 piglets were viremic and shed virus in nasal swabs, whereas only 71.4% and 38.1% of the T02 group were viremic or shed virus, respectively. Piglets from T02 had significantly higher numbers (p < 0.0001) of IFN-γ producing lymphocytes compared to T01. At necropsy, differences in gross and histologic lung lesions were statistically significant (p = 0.012 and p < 0.0001, respectively) between the two groups. Hence, this MLV vaccine administered to 1-day-old piglets was able to protect piglets against PRRSV infection at weaning.