The objectives of the experiment were to evaluate the effects of oral Ca supplementation and injectable butafosfan plus cyanocobalamin on mineral and energy metabolism. Two hundred eight multiparous Holsteins were randomly assigned in a 2 × 2 factorial arrangement: Negative Control (NC = 52), which received 3 subcutaneous (SC) injections of 25 mL of saline solution at 0, 3, and 7 DIM; Oral Ca (OC = 52), which received orally 2 doses of 350 mL (50 g of Ca) as Ca formate at 0 and 1 DIM; Cyanocobalamin plus Butafosfan (CB = 52) which received 3 SC injections of 25 mL of cyanocobalamin (0.005 mg/mL) plus butafosfan (0.1 g/mL) at 0, 3, and 7 DIM; and Positive Control (PC = 52), which received Ca formate and cyanocobalamin plus butafosfan. Daily milk yield was recorded during the first 100 DIM. Milk was sampled and analyzed in the first 2 weeks postpartum. Blood was sampled at 3, 7 and 14 DIM to analyze β-hydroxybutyrate (BHB) and at 0, 12, 24, 36 and 72 h postpartum to analyze ionized Ca (iCa). Clinical evaluations on d 1, 3, 7 and 14 were performed to determine incidence of diseases. Data were analyzed using the MIXED and GLIMMIX procedures of SAS. Cows which orally received OC had lower (P < 0.01) milk yields than control ones (47.48 vs. 48.41 kg/d; SEM = 0.22), and cows supplemented with CB had higher (P < 0.05) yields than non-treated ones (48.34 vs. 47.55 kg/d; SEM = 0.26), with no (P > 0.10) interaction. Milk composition and BHB concentrations did no differ (P > 0.10) among treatments. Concentrations of iCa were higher at 12h (P = 0.08) and 36h (P < 0.01) in the OC treatment and at 36h (P = 0.05) in the CB treatment, with (P = 0.05) interaction at 36h. The incidence of subclinical ketosis was lower in cows treated with OC (P = 0.03) than non-OC treated cows. There was a lower incidence of mastitis in cows treated with CB (P < 0.01) than non-CB treated ones. Other disorders did not differ (P > 0.10) among treatments. Our results show that OC supplementation increased iCa concentrations and reduced incidence of ketosis, but they had lower milk yields. Cows that received CB postpartum had increased milk yield and reduced incidence of mastitis.