Calf diarrhea leads to substantial economic losses in the livestock industry worldwide due to medical treatment costs, retarded growth performance, and even death. The objective of this study was to investigate changes in serum protein profiles and acute phase proteins in calves with diarrhea and identify the association between these changes and diarrhea. A total of 185 Korean beef calves were used and divided into 3 groups by age: 1 to 10 days (n = 46), 11 to 20 days (n = 65), and 21 to 30 days (n = 74). Blood and fecal samples were collected from each calf. Serum concentrations of total protein, protein fractions (albumin, α1-globulin, α2-globulin, β-globulin, and γ-globulin), haptoglobin (Hp), and serum amyloid A (SAA) were analyzed. Compared to calves without diarrhea, calves with diarrhea had significantly lower albumin concentrations at 11 to 20 days and 21 to 30 days of age (P = 0.017 and P = 0.000, respectively) and significantly higher α1-globulin fractions at 21 to 30 days of age (P = 0.01). Interestingly, α2-globulin fractions were significantly higher in diarrheic calves in all age groups, whereas γ-globulin fractions were significantly lower in calves with diarrhea aged 1 to 10 days, compared with normal animals. In calves with diarrhea, the concentration of Hp was significantly higher, whereas SAA levels were not different between normal and diarrheic calves. In addition, a positive correlation was found between α2-globulin and Hp (P = 0.0004). Taken together, these results provide useful information about the use of serum protein profiles and Hp as prognostic and diagnostic markers for animal health status.