Long distance transportation can be a significant source of stress to cattle and is associated with increased risk of bovine respiratory disease (BRD). The administration of a nonsteroidal anti-inflammatory drug (NSAID) has been shown to reduce stress following long distance transport. The objective of this study was to compare performance, health, accelerometer activity, and well-being between calves receiving either tildipirosin (Zuprevo 18%; Merck Animal Health, Madison, NJ) alone or in combination with transdermal flunixin (BANAMINE Transdermal Pour-on Solution; Merck Animal Health, Madison, NJ) on arrival at the feedlot. Three hundred eighty-four polled, Continental × English, and English crossbred bulls (n = 199) and steers (n = 185) were enrolled into one of two treatments: 1) tildipirosin administered in the neck as a single dose of 4 mg/kg only (PLBO) 2) tildipirosin in combination with transdermal flunixin applied to the dorsal midline at a dose of 3.3 mg/kg (FTD). Outcomes measured were average daily gain (ADG), dry mater intake (DMI), gain to feed, morbidity, mortality, accelerometer activity data, and a daily visual analog scale (VAS) assessment of well-being. Body weight (BW) was determined by weighing individual animals; ADG was calculated as initial BW—final BW / total days on feed; DMI was calculated as daily pen feed allocation—feed remaining at next feeding / number of calves in the pen; and gain to feed was calculated as pen level ADG / pen level DMI. The VAS used was a 100 mm line anchored at each end by descriptors of “no pain” or “severe pain”. Statistical analysis was performed using JMP 13 computer software using pen as the experimental unit, lot number as a random variable, and treatment as a fixed variable. There was no treatment effect on DMI (P = 0.51). During the first 14 d on feed, FTD calves had a lower ADG of 0.90 kg/d compared with 1.33 kg/d in the PLBO group (P = 0.05). There were no differences observed in morbidity and mortality between groups (P = 0.29). There were no treatment differences from activity data (P = 0.19). The VAS assessment showed a significant time × treatment interaction (P < 0.001). During the first 36 h after treatment administration, the FTD-treated calves had lower VAS scores [6.23 (95% CI: 5.27–7.20) compared with 7.28 (95% CI: 6.32–8.24)] than PLBO (P < 0.05). Results suggest that FTD-treated calves showed less signs of pain the first 36 h postdrug application relative to PLBO calves.