Calves experiencing dystocia frequently suffer from tissue injury and associated inflammation and pain. The study objective was to conduct a randomized controlled field trial to evaluate the effect of implementing a novel program that includes initial assessment of newborns using the VIGOR Scoring System (U of Guelph) followed by provision of a non-steroidal anti-inflammatory (NSAID) to calves with low vigor scores, on outcomes reflecting calf well-being and health. The study was conducted in the summer of 2017 on a 5,000-cow dairy in MN. Live born calves underwent enrollment within 3 h of birth (T0), including recording of weight and rectal temperature, collection of a venous blood sample, vitality assessment using the VIGOR System and colostrum feeding. The calf was then randomly assigned to either the treatment (TX) or control program (CON). Within the TX program, calves with a low VIGOR score (<21) were administered a gel capsule per os containing meloxicam (approximately 1 mg/kg). Between 24 and 36 h post-enrollment (T24) calves were reassessed using the VIGOR system, temperature recorded and a second blood sample collected. Paired (T0 and T24) plasma samples from 300 randomly selected calves were submitted for determination of plasma prostaglandin E₂ (PGE_2, pg/mL) and cortisol (ng/mL) concentrations. Of 1,483 calves enrolled (CON = 760; TX = 723), 68% and 32%, respectively, achieved a high (≥21) or low (<21) VIGOR score at T0. Multivariable linear regression models showed that at T0, calves with low VIGOR scores were heavier, were from calvings with higher dystocia scores (DS; 0 to 5) and had increased plasma PGE₂ concentrations (BWt = 40.2 kg; DS = 0.50; log₁₀PGE₂ = 1.63) as compared with calves with high VIGOR scores (BWt = 39.4 kg; DS = 0.37; log₁₀PGE₂ = 1.53) (P < 0.05). Meloxicam treatment of low VIGOR calves at T0 resulted in a larger reduction and lower plasma PGE₂ concentrations by T24 (log₁₀PGE₂ = 0.76), as compared with untreated low VIGOR calves (log₁₀PGE₂ = 0.99). We conclude that newborn calves with a low VIGOR score experienced increased inflammation as compared with calves with a high VIGOR score, and that meloxicam treatment of low VIGOR calves significantly alleviated inflammation by 24 h of age.