Feeding high-concentrate diets to dairy cows increases the risk of rumen fermentation disorders, such as subacute ruminal acidosis (SARA). SARA might induce perturbations in the systemic metabolism. Clay minerals have shown the potential to counteract negative effects of high-concentrate feeding. This study investigated if supplementing concentrate-rich diets with a clay-mineral based mix (CM) modulates the plasma metabolome in dairy cows experiencing SARA. Eight ruminally cannulated nonlactating Holstein cows were arranged according to a change-over design, receiving either 50 g of CM per day or no additive (CON) (n = 8 per treatment). The CM was mixed and fed with the respective concentrates. Cows were first fed with a pure forage diet (Baseline), followed by 2-intermittent 65%-concentrate-diet phases (SARA 1, SARA 2; 1 and 2 weeks duration, respectively). SARA 1 and 2 were separated by a 1-week recovery, in which the pure forage diet was fed. During the Baseline and SARA 1 blood samples were collected and a targeted ESI-LC-MS/MS-based metabolomics approach was carried out. Statistical analysis was performed using the MIXED procedure of SAS, including the feeding phase and the diets (CON, CM), as well as a possible interaction between them, as fixed effects and run and cow as random effects. SARA caused a decrease in several amino acids, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins (P < 0.05). Cows receiving CM had higher concentrations of several amino acids (i.e., glycine, isoleucine, lysine, methionine, and threonine; P ≤ 0.01) and phosphatidylcholines with diacyl-residues (P ≤ 0.10) than CON-cows. In addition, lower concentrations of histamine and spermine were detected (P < 0.01). Data suggests that the induction of SARA caused strong changes in the plasma metabolome. Furthermore, CM may reduce negative effects of high-concentrate diets by counteracting SARA-induced perturbations in the systemic metabolism.