The objective of this study was to delineate a model for chronic stress by evaluating physiological and hematological alterations in cattle administered: 1) 0.5 mg/kg BW dexamethasone (DEX) once daily at 10am for 3 d consecutively, or 2) 0.3 µg/kg BW corticotropin releasing hormone (CRH) and 1 µg/kg BW vasopressin (VP) twice daily at 10am and 10pm for 3 d consecutively. Twelve (n = 6) beef steers (BW = 389 ± 11kg) were stratified by BW, assigned randomly to treatment, and fitted with indwelling rectal temperature (RT) devices and jugular catheters, before relocation into individual stanchions in an environmentally-controlled facility. Blood samples were collected at 0.5-h intervals from −2 to 6 h relative to each 10am challenge. Serum was analyzed for cortisol concentration and whole blood samples were evaluated to profile hematological responses via automated hemocytometer. All data were analyzed using PROC MIXED with repeated measures and steer was the subject. A trt × time interaction (P < 0.001) was observed for RT, which increased transiently in both treatments following the 10am challenge time each d. However, the magnitude of the febrile response was greater (P < 0.001) for DEX. Likewise, serum cortisol increased transiently in response to both challenges, yet the cortisol increase was more pronounced for CRH-VP (trt × time; P < 0.001). On d 1, cortisol was 24.8 and 30.4 ng/mL for DEX and CRH-VP, respectively (trt × d; P < 0.001). Total peripheral blood leukocytes (PBL) were increased in both treatments; however, the PBL concentration was greater for DEX vs. CRH-VP from h 5 to 54 (trt × d; P < 0.001). The total PBL was associated with a corresponding increase in circulating neutrophils observed for DEX, but not CRH-VP on d 2 (12.2 vs. 7.2 × 103/μL) and 3 (11.7 vs. 6.6 × 103/μL; trt × d; P < 0.001). In contrast, eosinophils decreased (P < 0.001) sharply for DEX on d 1 and remained undetectable through d 3. These data suggest that exogenous administration of both DEX and CRH-VP alter RT and cortisol variables indicative of stress, while DEX may more strongly inhibit neutrophil translocation from peripheral blood, a key component of stress-induced immunosuppression.