The transition from late gestation to early lactation is the most metabolically challenging physiological stage in dairy ruminants. During this period, ruminants experience indeed some degree of negative energy balance (NEB) which is considered to increase susceptibility to mammary infections. The aim of this study was to determine the effect of NEB on mastitis in a dairy sheep model. Accordingly, 48 early-lactation dairy ewes from genetic lines for high and low somatic cell score (SCS) were allocated in 2 homogeneous subgroups: a NEB group which was energy restricted to 60% of their energy requirements during 15 d and a control-fed group. Ewes were monitored for milk production, SCS, body condition and blood metabolites. Previous study revealed an interaction between genetic line and energy restriction on several metabolic parameters and body condition. Indeed high-SCS ewes showed higher weight loss and increase of plasmatic β-hydroxybutyrate (BHB) and nonesterified fatty acids (NEFA) concentrations than low-SCS ewes, when facing NEB. Blood transcriptome analysis by RNA-seq was performed in 24 ewes at 3 time points: before the diet change, after 10 d of energy restriction, and 8 h upon an inflammatory mammary challenge. Transcriptomic and phenotypic data were integrated with a generalized partial least square discriminant analysis using mixOmics package framework (block PLS-DA). NEFA and BHB concentrations were the phenotypes that discriminated energy-restricted high-SCS ewes. The association between variables was computed using a similarity score, based on the coordinates of the variables on the axis defined by the principal components. The supervised analysis revealed a high correlation between milk fat content, fat-to-protein ratio and BHB and NEFA concentration (r > 0.8). Moreover, BHB and NEFA concentrations were highly correlated with the level of PDK4 and CPT1A expression (r > 0.9), which encode 2 key regulatory enzymes involved in respectively glucose oxidation and fatty acids β-oxidation. These results strongly suggest a genetic link between susceptibility to mastitis and metabolic adaptation to energy shortage.