Background: Salmonella enterica subsp. enterica is a public health issue related to food safety, and its adaptation to animal sources remains poorly described at the pangenome scale. Firstly, serovars presenting potential mono- and multi-animal sources were selected from a curated and synthetized subset of Enterobase. The corresponding sequencing reads were downloaded from the European Nucleotide Archive (ENA) providing a balanced dataset of 440 Salmonella genomes in terms of serovars and sources (i). Secondly, the coregenome variants and accessory genes were detected (ii). Thirdly, single nucleotide polymorphisms and small insertions/deletions from the coregenome, as well as the accessory genes were associated to animal sources based on a microbial Genome Wide Association Study (GWAS) integrating an advanced correction of the population structure (iii). Lastly, a Gene Ontology Enrichment Analysis (GOEA) was applied to emphasize metabolic pathways mainly impacted by the pangenomic mutations associated to animal sources (iv) . Results: Based on a genome dataset including Salmonella serovars from mono- and multi-animal sources (i), 19,130 accessory genes and 178,351 coregenome variants were identified (ii). Among these pangenomic mutations, 52 genomic signatures (iii) and 9 over-enriched metabolic signatures (iv) were associated to avian, bovine, swine and fish sources by GWAS and GOEA, respectively. Conclusions: Our results suggest that the genetic and metabolic determinants of Salmonella adaptation to animal sources may have been driven by the natural feeding environment of the animal, distinct livestock diets modified by human, environmental stimuli, physiological properties of the animal itself, and work habits for health protection of livestock.