Our objective was to compare the efficacy of oral propylene glycol, intravenous dextrose, or a combination of both in decreasing whole blood BHB concentrations in hyperketonemic early lactation Holstein cows. Multiparous Holstein cows were screened for hyperketonemia between 3 to 9 DIM using a handheld meter and enrolled at whole blood BHB concentration ≥1.2 mmol/L to 1 of 4 treatment groups: (1) 500 mL of a 50% dextrose solution (i.v.) once daily for 3 d (GLU, n = 9), (2) 300 mL propylene glycol as a drench once daily for 3 d (PG, n = 9), (3) a combination treatment of a 500 mL of 50% dextrose solution i.v. and 300 mL PG orally once daily for 3 d (GLU+PG, n = 8), or (4) an untreated control group (CTRL, n = 8). Blood samples were collected immediately before and at 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 h after administration of the first treatment and 3 times per wk thereafter. Morning blood samples were taken before feeding, at all other time points animals had access to TMR. Β-hydroxybutyrate concentrations were measured in whole blood, and plasma samples were analyzed for glucose, fatty acids, insulin, glucagon, and macromineral (Ca, Mg, K, Na, Cl, P) concentrations. Outcomes were analyzed using a repeated measures ANOVA (Proc MIXED, SAS 9.4). Least squares means (95% CI) of blood BHB concentrations between 1 h and d 11 relative to first treatment were 1.11 (0.95 to 1.30), 1.26 (1.07 to 1.47), 0.96 (0.81 to 1.13), and 1.53 (1.30 to 1.80) mmol/L for the GLU, PG, GLU+PG, and CTRL groups, respectively. Group GLU+PG showed the greatest magnitude and a more prolonged decrease in BHB concentrations compared with individual treatments. Plasma fatty acid and glucagon concentrations were lower 1 h after treatment in the GLU+PG group compared with CTRL and PG, and GLU+PG treatment was associated with a greater increase in plasma glucose and insulin concentrations 1 h after treatment compared with all other groups. Treatments did not lead to differences in plasma mineral concentrations. We conclude that treatments varied in the magnitude of blood BHB concentration reduction in hyperketonemic postpartum cows, with the greatest decline after treatment with a combination of intravenous glucose and oral PG.