Bovine respiratory diseases (BRD) have long been considered a serious problem that causes major economic losses in feedlot calves (FC). This study aimed to determine the diagnostic and prognostic effect of selected biological markers including, procalcitonin (PCT), neopterin (NP), proinflammatory cytokines (IL-1β, IL-8, TNF-α, IF-γ), haptoglobin (HP) and serum amyloid A (SAA) on FC with BRD under field conditions. Sixty-nine FC that were identified to be infected with Mannheimia haemolytica and Histophilus somni and had different clinical respiratory signs (diseased group) were selected for this study. In addition, 20 healthy FC have been selected as a control group. We have detected higher serum levels of PCT, NP, HP, SAA, IL-1β, IL-8, TNF-α and IF-γ in diseased FC group compared with the control group. All tested markers revealed a high level of discrimination between BRD infected FC and healthy ones (AUC > 0.90). Moreover, the obtained data showed a high degree of prognostic accuracy for PCT, NP, IL-8, HP, IF-γ and IL-1β in predicting treatment response of FC with BRD at the selected thresholds (AUC = 0.99, 0.99, 0.97, 0.93, 0.88 and 0.82, respectively). Significant inhibition was observed for the selected biochemical markers in treated FC 7 days post-treatment. In conclusion, this study showed that BRD in FC was associated with significant alterations in serum APPs, proinflammatory cytokines, PCT and NPT levels. Furthermore, it demonstrated that these serum biomarkers are much higher in FC with BRD compared to recovered ones. Our data suggest that the measurement of PCT, NPT, APPs and cytokines together with the clinical examination may be a useful diagnostic and prognostic tool for assessment of FC naturally infected with M. haemolytica and H. somni.