The objective of this study was to evaluate the effects of feeding rumen-protected glutamate during the periparturient period (d −21 ± 3 to d 21 ± 3 relative to calving) on apparent total-tract digestibility (ATTD), inflammation, metabolic responses, and production performance of dairy cows. Fifty-two multiparous Holstein cows were blocked by parity, body condition score, and expected calving date, and randomly assigned to one of the experimental diets with rumen-protected monosodium glutamate (RP-Glu; intestinally available Glu = 8.8%) or without RP-Glu (control) at d −21 ± 3 relative to expected calving date. The RP-Glu was fed at 4% and 3% of dietary dry matter, before and after calving, respectively. Prepartum diets contained 17.1% and 16.5% crude protein, and 13.1% and 13.3% starch, and postpartum diets contained 18.8% and 18.3% crude protein, and 22.5% and 22.7% starch on a dry matter basis, respectively for RP-Glu and control treatments. A subset of 19 cows was used to measure ATTD. Cows fed the RP-Glu had greater ATTD of dry matter (70.6 vs. 69.1%), crude protein (75.1 vs. 72.6%), and ether extract (66.0 vs 61.2%) on d 5 ± 1 after calving. Cows fed the RP-Glu also had greater dry matter intake (15.7 vs. 13.7 kg/d) on d 1 after calving. Cows fed the RP-Glu had greater plasma concentrations of Glu (4.60 vs. 3.89 µmol/dL) and insulin-like growth factor-1 (44.2 vs. 30.1 mg/mL), lower serum concentrations of free fatty acids (670 vs. 981 μEq/L) and total bilirubin (0.22 vs. 0.34 mg/dL), and lower plasma 3-methylhistidine concentration (1.28 vs. 1.50 μmol/dL) on d 4 after calving. However, these treatment effects observed between d 1 and d 5 ± 1 immediately after calving did not continue until d 21 after calving. Concentrations of serum amyloid A, serum haptoglobin, and plasma lipopolysaccharide binding protein were not affected by the treatment. In addition, no differences were observed for serum β-hydroxybutyrate concentration and milk yield during the postpartum period between the 2 groups, and cows fed the RP-Glu had a decreased lactose yield. These findings suggest that feeding RP-Glu during the periparturient period can increase digestive capacity and feed intake, and decrease mobilization of body fat and protein immediately after calving without increasing milk production.