Excessive adipose tissue (AT) lipolysis increases serum free fatty acids (FFA) and triggers AT inflammation predisposing cows to disease. Fetuin-A (FETA) is a FFA carrier and an acute-phase protein (APP) that enhances lipid-induced inflammation in AT of monogastrics. Little is known about its role and potential use as a biomarker in transition cows. We hypothesized that serum and AT FETA content increases as the periparturient period progresses and is enhanced by high lipolysis rate. Blood and subcutaneous AT were collected from 10 multiparous cows through the transition period at far off (FO; −51 ± 3d) and close-up dry (CU; −14 ± 2d), and early lactation (EL; 7 ± 0.5d). FETA was analyzed by ELISA in serum, and by RT-qPCR and protein blotting in AT. Contrary to our hypothesis, serum FETA concentration and AT gene and protein expression were greatest at FO compared with EL (P ≤ 0.05) when FFA concentration was the least (P < 0.01). Serum FETA concentration was 1.11 ± 0.08, 1.08 ± 0.08, and 0.98 ± 0.08 mg/mL at FO, CU and EL (P = 0.05), respectively, and was positively associated with serum albumin (r = 0.27; P = 0.03) and calcium (r = 0.32; P = 0.05). Circulating FETA was negatively associated with FFA (r = −0.25; P = 0.05) and BCS loss (r = −0.73; P < 0.001) over the transition period, and adverse health events at EL (r = −0.42; P = 0.05). AT FETA expression dynamics through FO, CU and EL was analogous to adipogenic and lipogenic genes PPARy, FASN, FABP4, and SCD1, and negatively correlated with AT inflammatory markers SPP1 (r = −0.46; P = 0.01) and CD68 (r = −38; P = 0.04). To test adipocyte inflammatory response to FETA in vitro, primary bovine adipocytes were treated with 0, 50, 100 or 200 μg/mL of FETA (8h), or LPS (25 ng/mL; 4h). Adipocytes treated with FETA had lower CCL2 expression than LPS (P = 0.03), and reduced adipocyte IL6 transcription (P = 0.01) when treated with 100 μg/mL of FETA compared with 0. These results indicate that FETA is a negative APP inversely linked to AT lipolysis and health events in transition cows. Contrary to monogastrics, FETA plays a beneficial role in AT inflammation in cows by modulating the expression of pro-inflammatory cytokines by adipocytes.