Dairy producers disbudding calves with caustic paste are less likely to provide pain control than those using cautery. Little research has been conducted on pain control for this method and no studies have specifically examined calves under a week of age although producers will commonly apply this product at this time. The objective of this study was to evaluate the efficacy of local anesthesia and nonsteroidal anti-inflammatory drug (NSAID) analgesia in very young dairy calves. 140 heifer calves aged 1–9 d were enrolled into 28 blocks and randomly allocated to 1 of 5 interventions: sham control; positive control (no pain control); lidocaine cornual block; meloxicam; and lidocaine cornual block and meloxicam. Data were analyzed using mixed models with a fixed effect for baseline values and a random effect for trial block. Compared with no local anesthetic, lidocaine reduced serum cortisol at 15, 30, 45, and 60 min post-disbudding (60 min; −138 pg/mL, 95% CI: −200 to −76 pg/mL). Cortisol values were not different between lidocaine treated calves and sham controls at these time points. At 60, 90, 120, and 180 min post-disbudding, calves treated with lidocaine and meloxicam had reduced cortisol compared with lidocaine alone (180 min post disbudding, −61 pg/mL, 95% CI −112 to −10 pg/mL), and values did not differ between lidocaine/meloxicam treated calves and sham controls at these time points. At 3–4 d post-disbudding, treatment with lidocaine and meloxicam tended to reduce haptoglobin (+0.16 mg/mL, 95% CI 0.00 to 0.32), but no differences were found between groups at 3 h and 6–7 d post-disbudding. At 60, 90, and 120 min post-disbudding, lidocaine treated calves had decreased pressure sensitivity (90 min, −2.26 kgf, 95% CI −3.15 to −1.37). No differences were seen in pressure sensitivity between groups at 180 min, 3–4- or 6–7-d post-disbudding. These findings suggest that the combination of local anesthesia with NSAID analgesia are beneficial at reducing pain indicators and inflammation in very young calves disbudded with caustic paste.