Hybrids between species frequently suffer from reduced fertility. Following the propagation of 672 yeast lines through 770 mitotic generations in which natural selection was minimized, we show that inter-species diploid hybrids can recover fertility spontaneously and rapidly to the level of parental lineages through whole-genome duplication. Although rare, these events occurred in hybrids between incipient species as well as between well-established species. Our results show that the instability of hybrid ploidy is a powerful mechanism to overcome species barriers.