Macleaya cordata extract (MCE), a phytogenic additive, is used in various species because of its multiple biological effects. These effects are linked especially to its major active compound sanguinarine, an isoquinoline alkaloid. To date, there is little information on its effects on horses. Our objectives were to determine whether a commercial MCE phytogenic additive is safe for horses and evaluate the effects of increasing inclusion rates of it on gut health and systemic inflammation of horses fed with a high-starch diet. The study design was a contemporary double 4 × 4 Latin square design. Eight healthy gelding ponies were used (8 experimental units per treatment, and a total of 32 experimental units). Dry matter intake was 1.75% body weight (BW) and starch intake was 2.2 g/kg BW per meal. Horses were randomly assigned into four treatments: Control, without MCE; S1, 1 mg MCE/kg BW; S1.5, 1.5 mg MCE/kg BW; and S2, 2 mg MCE/kg BW. Feed safety was determined by hemogram, leucogram, serum biochemical, and oxidative stress analyses. Systemic inflammation was measured by fibrinogen and gene expression of interleukins (IL) 6 and 10 in peripheral blood mononuclear cells (PBMC). The thickness of the right dorsal colon (RDC) wall was examined by abdominal ultrasonography as a variable related to gut health. Data were analyzed by PROC MIXED of SAS, and the means were compared using Tukey's test at 5% significance. RDC wall thickness, fibrinogen, IL-6, and IL-10 were analyzed by orthogonal polynomials and Pearson correlation. Serum albumin presented a lower value in S2 (2.97 g/dL) when compared to Control (3.10 g/dL) (P = 0.005), but albumin/globulin relation was not different among treatments. In orthogonal polynomial analyses, there were no differences among the systemic inflammatory variables; only RDC wall thickness values presented a linear response (R² = 0.223; P = 0.001). Pearson correlation showed a strong positive and significant correlation between IL-6 and IL-10 (R = 0.818; P < 0.001). The commercial MCE is safe for horses up to doses of 2 mg/kg. No systemic anti-inflammatory effects were observed, but the thinner intestinal wall in supplemented horses showed that the phytogenic additive had a local effect. We suggest that further studies must be done using this commercial MCE for horses.