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Sodium-glucose co-transporter 2 inhibitors like canagliflozin (CFZ) have shown promise in preventing hyperinsulinemia-associated laminitis in horses, but data on pharmacokinetics, tolerability, and controlled studies are limited. This randomized, open-label, placebo-controlled, crossover study evaluated these aspects of CFZ treatment in eight healthy Standardbred mares. Each horse received single supratherapeutic oral doses of CFZ (1.8 mg/kg or 3.6 mg/kg) and placebo, with a two-week washout between treatments. A graded glucose infusion (GGI) was administered post-treatment to evaluate glucose and insulin responses. Plasma CFZ, glucose, insulin, urinary glucose, serum biochemistry, and urinalysis samples were collected over 72 h post-treatment. For CFZ 1.8 mg/kg, median C_max was 2623 ng/mL, T_max 2.2 h, and T_1/2Z 21.8 h; for 3.6 mg/kg, C_max was 4975 ng/mL, T_max 2.8 h, and T_1/2Z 23.0 h. The pharmacokinetics of CFZ displayed dose-proportionality across the two tested doses. Insulin and glucose responses to a GGI, measured by the area under the concentration-time curve (AUC), were similar between CFZ doses but significantly reduced compared to placebo (p < 0.001). Specifically, mean glucose AUC for CFZ treatments was approximately 14–15 % lower, and mean insulin AUC 22–29 % lower, than for placebo. For CFZ-treated horses, mean urinary glucose concentrations ranged from 277 to 347 mmol/L at 24, 48, and 72 h post-administration, with no significant differences between dose levels. No clinical signs of adverse effects were observed, although a significant increase in GLDH levels compared to placebo (p < 0.05) was observed with the CFZ 3.6 mg/kg dose.