The effect of postpartum meloxicam administration on ewe inflammatory status and plasma fatty acid (FA) and oxylipid concentrations were evaluated in 34 Hampshire and Hampshire × Suffolk ewes rearing singles or twins. After lambing, ewes (94 ± 17 kg BW) were sequentially assigned within type of birth to control (n = 16) or meloxicam orally administered on d 1 and 4 of lactation (MEL; 90 mg, n = 18). Blood was sampled on d 1 (before treatment) and d 4, and plasma was analyzed for haptoglobin (Hp) by colorimetric assay, FA profile by LC-MS, and oxylipids by LC-MS/MS. Results were analyzed in a mixed model with d 1 values as covariates. Plasma Hp concentrations tended to be less for MEL ewes (P = 0.06), and a covariate x treatment effect (P = 0.04) showed that CON ewes with greater d 1 Hp concentrations were also elevated on d 4, which was not the case for MEL. Among FA, MEL increased arachidonic acid (AA) concentration by more than 4-fold in ewes rearing singles (P < 0.01 main effect and interaction). MEL decreased concentrations of 9,10-DiHOME, PGF_2α, 8-iso-PGE₂, and 8,9-DHET (P < 0.05). Nine oxylipids had interactions of treatment with d 1 Hp (P < 0.05), all of which revealed positive associations between d 1 Hp and d 4 oxylipid concentrations for CON, but neutral or negative relationships for MEL. MEL decreased 13-HODE/13-oxoODE (P = 0.04), tended to increase 9-HODE/9-oxoODE ratio (P = 0.06; both dependent on d 1 values), and tended to decrease 13-HODE/9-HODE ratio (depending on d 1 Hp, P = 0.08), indicating progressive metabolism of linoleic acid-derived oxylipids occurred by enzymatic oxidation after MEL treatment. The diversity of affected oxylipids suggested that MEL not only inhibited cyclooxygenase activity, but may also have reduced cytochrome P450 and nonenzymatic oxidative reactions, potentially due to an improved redox state. In conclusion, postpartum MEL treatment of ewes decreased plasma concentrations of Hp and several oxylipids, with the greatest effect in ewes with biomarkers reflecting a greater inflammatory state before treatment.