Dehorning is a commonly performed husbandry procedure in cattle to limit injury and conform to modern facility design. Prior research provides evidence that dehorning results in increased nociception and stress through changes in behavioral, neuroendocrine, and physiological responses. Alterations in these actions allow investigators to evaluate pain and stress reducing practices. In addition to improved welfare strategies including institution of polled breeding programs and conducting the procedure on young animals, calves may benefit from the administration of analgesics including local anesthetics, non-steroidal anti-inflammatory drugs (NSAIDs), and α2-agonists. Reviews of the literature have indicated a multimodal approach including local anesthetics and NSAIDs may be the optimal strategy to mitigate the negative response following dehorning. Since no analgesic products are currently labeled for cattle in the United States, providing an appropriate and effective analgesic remains challenging. As such, we have studied the pharmacokinetics and clinical efficacy of different NSAIDs in calves undergoing cautery dehorning. Initially, we evaluated the pharmacokinetics and clinical efficacy of firocoxib following cautery dehorning in calves. Although this NSAID was well absorbed orally in calves and inhibited prostaglandin for 48 h compared to placebo treated controls, minimal analgesic effects were observed using a study dose of 0.5 mg/kg. Subsequently we evaluated the pharmacokinetics and clinical efficacy of carprofen in a similar cautery dehorning study. Using the approved anti-inflammatory dose of 1.4 mg/kg in the European Union, oral carprofen was well absorbed and moderately inhibited prostaglandin for up to 96 h, however minimal analgesic effects were observed. Following descriptions of the pharmacokinetics and effects of oral carprofen and firocoxib, a comparison of four NSAIDs (carprofen, flunixin meglumine, firocoxib, and meloxicam) orally administered at 2.0 mg/kg was conducted as a field trial. Although responses indicative of pain and stress reduction varied among the treatment groups, evidence from the field trial indicate meloxicam may have superior potency compared to the other evaluated NSAIDs. Moreover, the use of oral meloxicam provides optimal analgesia for 24 h following a one-time dose of 2.0 mg/kg.