OBJECTIVE To quantify acute immunologic and metabolic responses of beef heifers following topical administration of transdermal flunixin meglumine (TDFM) at various times relative to bovine herpesvirus 1 (BHV1) and Mannheimia haemolytica challenges. ANIMALS 32 beef heifers (mean body weight, 170 kg). PROCEDURES Heifers were assigned to 1 of 4 groups. Heifers in the control group did not receive TDFM, whereas 1 dose of TDFM (3.3 mg/kg) was topically applied to heifers of groups A, V, and B at –144, –72, and 0 hours. All heifers were inoculated with 1 X 108 plaque-forming units of BHV1 in each nostril at –72 hours and with 1.18 X 106 CFUs of M haemolytica intratracheally at 0 hours. Vaginal temperature was recorded and blood samples were collected for quantification of select immunologic and metabolic biomarkers at predetermined times from –144 to 360 hours. RESULTS Mean vaginal temperature was similar between group A and the control group. Mean vaginal temperatures for groups V and B were generally lower than that for the control group following BHV1 and M haemolytica challenges, respectively. Mean neutrophil oxidative burst capacity and L-selectin expression at 0 hours were significantly decreased for group V relative to the other groups. Other biomarkers did not differ among the groups at any time. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that topical administration of TDFM to beef cattle effectively alleviated pyrexia without adverse effects on acute immunologic or metabolic responses when TDFM was administered at the same time as, but not before, respiratory pathogen challenge.