To determine whether previous plane of milk replacer nutrition (PON) and M. haemolytica (MH) dose influences metabolic responses to a combined viral-bacterial respiratory challenge, Holstein calves (1d of age; n = 30) were assigned to treatments in a 2 × 3 factorial with preweaned PON and dose of MH as main effects (n = 5/treatment). Calves were fed either a low (LPN; n = 15) or a high PON (HPN; n = 15) from birth through weaning. Calves fed the LPN were fed 445g DM/d of milk replacer until weaning, and HPN calves were fed 830g DM/d of milk replacer from 1 to 10d and 1080g from 11d until weaning. Calf starter and water were offered ad libitum. Calves were step-down weaned beginning at 54d and moved into an enclosed barn at 70d. Indwelling jugular catheters were inserted at 80d. Calves were challenged with 1.5 × 10⁸ PFU/mL/nostril of bovine herpesvirus-1 (BHV-1) at 81d and with 10⁶, 10⁷, or 10⁸ cfu of MH at 84d. Blood samples were collected at varying intervals respective to BHV-1 and MH challenges. Body weights at 70d were different (P < 0.01) between LPN and HPN calves (62.2 vs 81.2 ± 2.67 kg, respectively). Although HPN calves consumed more calf starter (P < 0.01) during the challenge, there were no differences (P ≥ 0.42) in ADG or when intake was expressed per kg BW^0.75. Glucose concentrations were greater (P ≤ 0.02) in HPN compared with LPN calves during both BHV-1 (61.1 vs 57.5 ± 1.01 mg/dL, respectively) and MH challenges (57.8 vs 53.5 ± 1.13 mg/dL, respectively). Following the MH challenge, calves receiving 10⁸ MH had the greatest (P = 0.05) NEFA concentrations. During the BHV-1 challenge, there was a time × PON interaction (P = 0.02) for plasma urea N concentrations, where LPN calves had greater (P = 0.02) concentrations at 72 h. Glucose concentrations were reduced among LPN calves throughout the respiratory challenge, and calves receiving 10⁸ MH mobilized more lipid reserves after the MH challenge suggesting calves fed a LPN during preweaning and calves receiving a 10⁸ MH dose results in a more severe response to a viral-bacterial respiratory challenge.