Interspecies hybrids often show some advantages over parents but also frequently suffer from reduced fertility, which can sometimes be overcome through sexual reproduction that sorts out genetic incompatibilities. Sex is however inefficient due to the low viability or fertility of hybrid offspring and thus limits their evolutionary potential. Mitotic cell division could be an alternative to fertility recovery in species such as fungi that can also propagate asexually. Here, to test this, we evolve in parallel and under relaxed selection more than 600 diploid yeast inter-specific hybrids that span from 100,000 to 15 M years of divergence. We find that hybrids can recover fertility spontaneously and rapidly through whole-genome duplication. These events occur in both hybrids between young and well-established species. Our results show that the instability of ploidy in hybrid is an accessible path to spontaneous fertility recovery.