Bovine respiratory disease (BRD) is one of the leading causes of morbidity and mortality in dairy calves. Identification of reliable biomarkers of naturally occurring BRD is essential for ensuring early diagnosis and treatment of calves and monitoring treatment efficacy. This need is punctuated, especially in mild to moderate cases that would greatly help to decrease recurrence and the overall prevalence of BRD. The present study was conducted to investigate the changes in serum concentrations of haptoglobin (Hpt) and serum amyloid A (SAA) and association between oxidative stress and acute phase proteins (APPs) in BRD. Hpt and SAA levels significantly increased (P < .01) in BRD stressed calves as compared to healthy subjects. There was a significant decrease (P < .01) in serum albumin (Alb) concentration of infected calves as compared to controls. The oxidative stress markers revealed a significant (P < .01) increase in lipid peroxidation (LPO) and a concurrent decrease in activities of superoxide dismutase (SOD), reduced glutathione (R-GSH) and catalase (CAT) in BRD. A significant correlation among APPs, extent of oxidative stress and clinical score (CS) of calves was depicted. A stepwise decrease in Hpt and SAA and increase in Alb was observed in infected calves post-treatment. These results suggest implication of oxidative stress in enhancing APPs and monitoring of APPs as a potential complement to clinical assessment of treatment in calves with naturally occurring BRD. Hpt may be useful as the most sensitive biomarker in BRD. However, the combined use of Hpt and oxidative stress biomarkers would greatly improve the diagnostic accuracy.