One practical application of genome‐scale metabolic reconstructions is to interrogate multispecies relationships. Here, we report a consensus metabolic model in four yeast species (
Saccharomyces cerevisiae
,
S. paradoxus
,
S. mikatae
, and
S. bayanus
) by integrating metabolic network simulations with
RNA
sequencing (
RNA
‐seq) datasets. We generated high‐resolution transcriptome maps of four yeast species through
de novo
assembly and genome‐guided approaches. The transcriptomes were annotated and applied to build the consensus metabolic network, which was verified using independent
RNA
‐seq experiments. The expression profiles reveal that the genes involved in amino acid and lipid metabolism are highly coexpressed. The diverse phenotypic characteristics, such as cellular growth and gene deletions, can be simulated using the metabolic model. We also explored the applications of the consensus model in metabolic engineering using yeast‐specific reactions and biofuel production as examples. Similar strategies will benefit communities studying genome‐scale metabolic networks of other organisms.