Caustic paste disbudding is becoming more commonplace in North America, but few studies have evaluated pain control for this procedure. The objective of this clinical trial was to evaluate the effects of either a lidocaine cornual nerve block or a topical anesthetic incorporated into caustic paste on the acute pain of caustic paste disbudding. Seventy-two Holstein-Friesian calves housed in groups with an automated milk feeder were enrolled into 18 replicates balanced on age and assigned to one of 4 treatments: sham (S), a placebo paste and a saline cornual block; topical (T), a novel caustic paste containing lidocaine and prilocaine, and a saline cornual block; cornual block (B), commercial caustic paste and a lidocaine cornual nerve block; and positive (P), commercial caustic paste and a saline cornual block. All calves received 0.5 mg/kg meloxicam SC at the time of the block. Researchers were blinded to treatment group. Primary outcomes were validated pain behavior responses, and pain sensitivity measured by algometry. Secondary outcomes consisted of respiratory and heart rate, latency to approach the evaluator, play behavior, feeding behavior, and standing and lying bout characteristics. Data were analyzed using linear, Poisson, and negative binomial regression models. Cornual-blocked calves had less pain sensitivity to 180 min after disbudding than all other groups (P < 0.001); T and P calves had more pain sensitivity than S calves for the same time period (P < 0.001). Compared with T and P calves, B and S calves had fewer pain behaviors until 120 min post-disbudding (P < 0.05) and decreased respiratory and heart rates (P < 0.01). S calves exhibited more play behavior than other groups (P < 0.001) and tended to have a shorter latency to feed than T or P calves (P < 0.10). Caustic paste appears to be acutely painful for at least 180 min, and this is reduced by a cornual nerve block but not by our novel paste. We recommend that calves disbudded with caustic paste receive local anesthetic by a cornual nerve block to mitigate acute pain.