Gene orthology inference across species is crucial to identify gains and losses of functions. The discovery in axolotl (Ambystoma mexicanum) of a regeneration-associated gene identified as either Kazald1 or Kazald2 led us to investigate its evolution via an extensive cross-species analysis. Molecular phylogeny inference identified the gene as Kazald2 and revealed an undescribed four-member Kazald gene family in jawed vertebrates. Synteny comparisons demonstrated that this family originated in the two-round whole-genome duplication event. Additionally, vertebrate-wide comparisons of Kazald expression, validated in tissues of axolotl, zebrafish, and sharks, uncovered seemingly ancestral connections conserved over jawed vertebrate evolution, and suggested novel putative roles within specific lineages. Our study demonstrates the establishment of the Kazald family in the jawed vertebrate ancestor and elucidates the asymmetry of gene fates of its members. This provides a comprehensive report of this formerly undescribed gene family, offering a solid foundation for its study in diverse species.