Objectives of the study were to compare the effects of 2 metritis treatments on metabolite concentrations and rumination/activity before and after diagnosis. Cows were examined at 4, 6, 8, 10 and 12 DIM for metritis (fetid, watery, red/brown uterine discharge). On the day of enrollment (d 0), cows were paired by parity and severity of metritis [metritis vs. puerperal metritis (rectal temperature ≥ 39.5°C)] and assigned randomly to Ampicillin (AMP) or Ceftiofur Crystalline Free Acid (CCFA) treatments. Cows enrolled in the AMP (n = 307) treatment were moved to a hospital pen where they were treated once daily for 5 d and were moved back to their original pen 72 h after the last treatment (d 7). Cows enrolled in the CCFA (n = 306) treatment remained in their original pen and received 2 doses of CCFA, 72 h apart. Contemporary healthy cows (POS = 636) were paired by parity with metritic cows and were enrolled in the study. A subgroup of cows (AMP = 95, CCFA = 106, POS = 122) had blood sampled on d 0, 1, 2, 6, 7, 8, and 14 after enrollment for determination of glucose, nonesterified fatty acid (NEFA), and BHB concentrations. Automated devices that record rumination/activity were fitted on a subgroup of animals (AMP = 102, CCFA = 90, POS = 416) 21 d before expected calving date. Cows treated with AMP had greater glucose concentration (67.8 ± 5.1 vs. 64.4 ± 5.1 mg/dL; P < 0.01) and reduced BHB concentration (750.8 ± 38.5 vs. 919.7 ± 36.8 μmol/L; P < 0.01) from d 1 to 8 than cows treated with CCFA. Concentration of NEFA from d 1 to 8 did not (P = 0.85) differ between treatments. Treatment (P = 0.74) and the interaction between treatment and day relative to enrollment (P = 0.15) did not affect rumination. The interaction between treatment and day relative to enrollment affected (P < 0.01) activity because on d 7 (458.2 ± 4.6, 432.3 ± 4.0 arbitrary units) and 8 (445.0 ± 4.7, 428.5 ± 5.0 arbitrary units) post-enrollment cows treated with AMP had greater activity than cows treated with CCFA. In conclusion, treatment of metritic cows with AMP vs. CCFA mildly altered metabolic parameters and activity, but their biological significance are likely negligible.