Simple SummarySurgical procedures are routinely performed in calves, both under sedation and general anesthesia. The availability of analgesic drugs is limited in food-producing animals, making their perioperative management challenging. Few are the studies assessing the extent of pharmacological antinociception obtained when administering sedative and analgesics in cattle and the tools used are mainly qualitative. With the present study, we aimed at assessing the antinociceptive effect of butorphanol with or without detomidine in calves, using the modulation of the trigeminocervical reflex threshold as the main outcome. The trigeminocervical reflex threshold is a quantifiable nociceptive reflex that can be used to assess the modulation of pain processing. As secondary aims, physiological and behavioral effects of the administered treatments were evaluated, and the temporal profile of drug activity was described. This study provides quantitative evidence of the efficacy of butorphanol administered alone or combined with detomidine in calves. The presented findings can now contribute to optimizing the application of these drugs in clinical practice.Abstract(1) Background: The diagnostic and therapeutic procedures performed under sedation or general anesthesia in bovines are numerous. The analgesic drugs that can be legally used are few, making perioperative analgesia challenging. (2) Methods: Calves were administered butorphanol 0.1 mg kg−1alone (SB) or combined with 0.02 mg kg−1of a detomidine (DB) IV. The antinociceptive effect (trigeminocervical reflex threshold (TCRt)), as well as the behavioral (sedation and excitation) and physiological (heart and respiratory rate) changes were investigated. Five time windows were defined: BL (30 min pre-injection), T1 (0–30 min post-injection (PI)), T2 (31–60 min PI), T3 (61–90 min PI) and T4 (91–120 min PI). (3) Results: Both groups had a significative increase in TCRt at T1-T4 compared to the BL. The TCRt was significatively higher in DB than in SB at T1, T2 and T4. Heart rate decreased significatively in DB compared to that in BL. Calves were significantly more sedated in the DB group, and significantly more excited in the SB group compared to the BL. (4) Conclusions: Butorphanol alone has a statistically significant antinociceptive effect, but it elicits marked excitation, limiting its clinical applicability under this dosing regimen. The co-administration of detomidine eliminated the excitatory effect and induced consistent sedation and a significantly more pronounced antinociceptive effect.