The use of local anesthesia and a nonsteroidal anti-inflammatory drug (NSAID) can reduce indicators of pain and inflammation and encourage self-rewarding behavior in calves following disbudding. Although the use of sedation may be recommended as a best practice for disbudding, there is little research in this area. The objective of this study was to evaluate the effects of xylazine sedation in conjunction with a local anesthetic and an NSAID in calves undergoing cautery disbudding. One hundred twenty-two group-housed female and male Holstein calves fed milk with automated feeders, aged 13 to 44 d, were enrolled over 9 replicates and randomly allocated to 1 of 2 treatments: (1) sedated: lidocaine cornual nerve block, 0.5 mg/kg meloxicam (administered subcutaneously) and 0.2 mg/kg xylazine (administered intramuscularly), or (2) nonsedated: lidocaine cornual nerve block and meloxicam. Outcomes collected consisted of feeding behavior (collected using automated milk feeders), latency to drink milk following disbudding, play behavior (induced by adding bedding), lying behavior, mechanical nociceptive threshold (MNT, measured using a pressure force algometer), struggling behavior during disbudding, length of time to administer the nerve block, length of time to disbud, and serum haptoglobin concentrations. Data were analyzed using mixed models with a fixed effect for baseline values and a random effect for trial replicate. Linear regression was used to assess continuous outcomes, logistic regression for binary outcomes, and Poisson and negative binomial models for count data with negative binomial models used if the over dispersion term was significant. There were no detected differences between the treatment groups in mean daily milk consumption in the 72-h following disbudding. Sedated calves had reduced average milk drinking speed from 0 to 24 h and 24 to 48 h following disbudding compared with nonsedated calves, but no difference was detected from 48 to 72 h. Sedated calves had reduced MNT at 0, 60, and 240 min after disbudding, but no differences were detected between groups at 24 h after disbudding. Nonsedated calves had 4.5 times the odds (95% CI: 1.5-13.2) of struggling more than twice during the disbudding procedure compared with sedated calves, and it took less time to administer a nerve block to sedated calves compared with nonsedated. At +3 h, nonsedated calves were 79 times (95% CI: 22.4 to 279.2) more likely to play compared with sedated calves, and 24 h after disbudding, sedated calves were 2 times more likely to play compared with nonsedated calves (95% CI: 0.93-4.3). The results indicate that calves sedated with xylazine for cautery disbudding responded less to painful stimuli (disbudding and MNT) both during and following the procedure and had a higher rate of play behavior 24 h following sedation compared with the nonsedated calves, but xylazine may also have a prolonged carryover effect that affects suckling behavior for 48 h following sedation.