Recombinant bovine somatotropin (rbST) restores homeorhetic mechanisms to support lactation; however, the effects of rbST on the bovine metabolome and lipidome are undefined. Therefore, 8 multiparous lactating Holstein cows (195 ± 34 DIM) were enrolled in a 2 × 2 replicated Latin square design with 14 d periods. Cows received a single injection of rbST (Posilac; Elanco Animal Health, Indianapolis, IN; 0.062 mg/kg BW) or no injection (CON) at period start. On d 8, 9 and 10, an epinephrine challenge (EC; 1.6 µg/kg BW), insulin tolerance test (ITT; 0.1 IU/kg BW), and liver biopsy were performed, respectively. Plasma glucose and total fatty acids (FA) were measured. Plasma was also processed for metabolomics or lipidomics using mass spec. Univariate and multivariate ANOVA were performed. Omic data were generalized log-transformed. Somatotropin elevated milk yields compared with CON (P < 0.01) despite lower DMI (P < 0.05). Milk fat yield and percent, and milk protein and lactose yields were higher in rbST cows (P < 0.01). Plasma total FA levels were increased with rbST (peaking at d 8; P < 0.01). At the start of the EC, rbST cows had 75% higher circulating total FA compared with CON (478 vs 119 µmol/L; P < 0.01) which increased post epinephrine (866 vs. 218 µmol/L for rbST and CON by 15 min, respectively; P < 0.01). Epinephrine responsiveness (change from baseline), and insulin-stimulated plasma glucose clearance and reductions in total FA were not modified by treatment. Plasma levels of oxoproline, glutamic acid, threonine, and fatty acids and their derivatives (e.g., linoleic acid, arachidonic acid, ethyl myristate, and eicosatrienoic acid) were higher in rbST cows (P < 0.05). The plasma lipidome was dynamically modified with treatment (218 out of 385 features; P < 0.05). Treatment with rbST decreased plasma mono-, di-, and triacylglycerols levels (e.g., MG-18:0, DG-18:0/16:0, and TG-16:0/14:0/16:1; P < 0.05). Similarly, many phosphatidylcholines and sphingomyelins were significantly lower in rbST cows by d 8 (P < 0.05). We conclude that rbST modifies the bovine plasma metabolome and lipidome with increased milk production.