This proof-of-concept study evaluated the effects of the anti-inflammatory drug meloxicam on markers of systemic inflammation and energy metabolism, neutrophil function, and endometritis. Cows received meloxicam (0.5 mg/kg SC (MEL) n = 20) once/d for 4 d (10–13 DIM) or were untreated (CON; n = 22). Blood samples were collected −7, 1, 3, 5, 7, 10, 11, 12, 13, 14, 18, 21, 28, and 35 DIM to measure serum haptoglobin (Hp), albumin, total protein, urea, hepatic enzymes (AST, GGT, GLDH), BHB, NEFA, Ca, glucose, and IGF-1. Neutrophil phagocytosis and oxidative burst were measured at 5, 10, 14, and 21, and endometrial cytology at 5, 10, 14, 21, 28 and 35 DIM. The effect of treatment was assessed with mixed linear regression models. MEL had lower Hp at 11, 12, and 13 DIM (0.2 ± 0.2, 0.3 ± 0.2, and 0.4 ± 0.2 g/L vs. CON 0.8 ± 0.3, 1.2 ± 0.4, and 1.1 ± 0.3 g/L, respectively; P < 0.05). BHB was lower in MEL at 11, 12, 13, and 14 DIM (0.6 ± 0.1, 0.7 ± 0.1, 0.5 ± 0.1, and 0.6 ± 0.1 mmol/L vs. CON 0.9 ± 0.2, 0.9 ± 0.2, 1.0 ± 0.4, and 0.8 ± 0.2 mmol/; P < 0.05). Serum IGF-1 was greater in MEL during treatment (0.84 ± 0.09, 0.81 ± 0.10, 0.83 ± 0.08, and 0.83 ± 0.09 μg/L vs. 0.76 ± 0.10, 0.67 ± 0.09, 0.65 ± 0.08, and 0.72 ± 0.07 μg/L; P < 0.03) and glucose was greater in MEL at 13 DIM (3.50 ± 0.10 vs. 3.01 ± 0.17 mmol/L; P = 0.04). Phagocytic activity (fluorescence intensity) was 27% greater (P = 0.04) in MEL at 14 DIM. Other metabolites and markers of inflammation were not different between treatments. The proportion of endometrial neutrophils was not different at 5, 10, 14, 21, 28, or 35 DIM (MEL 21 ± 5, 40 ± 6, 50 ± 6, 40 ± 7, 26 ± 8, and 15 ± 5% vs. CON 15 ± 5, 46 ± 7, 52 ± 6, 45 ± 6, 22 ± 5, and 14 ± 5%; P > 0.3). MEL attenuated systemic inflammation and improved indicators of energy balance but did not affect uterine inflammation.