The deletion of orphan response regulator CovR reduces the growth rate ofStreptococcus suisserotype 2 (S. suis2). In this study, metabolome and transcriptome profiling were performed to study the mechanisms underlying the poor growth ofS. suis2 caused by the deletion of orphan response regulator CovR. By comparingS. suis2 (ΔcovR) andS. suis2 (SC19), 146 differentially accumulated metabolites (upregulated: 83 and downregulated: 63) and 141 differentially expressed genes (upregulated: 86 and downregulated: 55) were identified. Metabolome and functional annotation analysis revealed that the growth of ΔcovRwas inhibited by the imbalance aminoacyl tRNA biosynthesis (the low contents of L-lysine, L-aspartic acid, L-glutamine, and L-glutamic acid, and the high content of L-methionine). These results provide a new insight into the underlying poor growth ofS. suis2 caused by the deletion of orphan response regulator CovR. Metabolites and candidate genes regulated by the orphan response regulator CovR and involved in the growth ofS. suis2 were reported in this study.