The aim of this study is to explore the impact of sodium butyrate on d-glutamyl- meso-diaminopimelic acid (iE-DAP)-induced liver inflammation in dairy goats during subacute ruminal acidosis (SARA) caused by high-concentrate feed. To achieve this aim, 12 lactating dairy goats were randomly divided into two groups: a high-concentrate feed group ( n = 6, concentrate/forage = 6:4) as the control group and a sodium butyrate (SB) with high-concentrate feed group ( n = 6, concentrate/forage = 6:4, with 1% SB by wt.) as the treatment group. A rumen pH below 5.6 lasted for at least 4 h/d due to long-term HC feeding. The concentration of iE-DAP was significantly lower (11.67 ± 3.85 μg/mL, and 7.74 ± 1.46 μg/mL, at the fourth h and sixth h of feeding, respectively) in the SB-treated group than that in the HC group (51.45 ± 5.71 μg/mL, and 18.31 ± 3.83 μg/mL, at the fourth h and sixth h of feeding, respectively). Meanwhile, SB significantly suppressed the mRNA expression of inflammatory genes (NOD1, RIPK2, TAK1, NF-κB/p65, ERK, JNK2, p38, IL-1β, TNF-α, CCL5, CCL20, CXCL12, FOS, β-defensin/LAP). Moreover, the protein expression of NOD1, p-IκBα, p-NF-κB/p-p65, p-ERK1/2, p-JNK, p-p38, and HDAC3 was significantly downregulated in the HC+SB group. In conclusion, iE-DAP-induced inflammation and liver disruption generated by the HC diet was mitigated by SB treatment.