Equine gastric ulcer syndrome (EGUS) is commonly treated with omeprazole, a proton pump inhibitor (PPI) that must be administered on an empty stomach, limiting its practicality. Potassium-competitive acid blockers (P-CABs), such as vonoprazan, represent an alternative class that offers advantages over PPIs in humans and may provide similar benefits in horses. This study evaluated the pharmacokinetics and effects on intragastric pH of a single vonoprazan dose. Six horses received 0.5 mg/kg and 1 mg/kg vonoprazan, 4 mg/kg omeprazole, and 60 mL water in a randomized, four-way balanced crossover design. Blood samples were collected before dosing and for 72 hours after administration. Drug concentrations were quantified using liquid chromatography–mass spectrometry, and pharmacokinetic parameters were determined via non-compartmental analysis. Intragastric pH was recorded continuously from 12 hours before to 24 hours after dosing. The percentage of time pH exceeded 4 was compared across treatments. For vonoprazan at 0.5 mg/kg and 1 mg/kg, Cmax values were 23.7 ± 14.0 and 55.8 ± 18.1 ng/mL, Tmax values were 0.875 (0.25–3.0) and 0.625 (0.08–1.0) hours, and HL-λz values were 5.74 ± 1.65 and 5.9 ± 1.86 hours, respectively. At 1 mg/kg, vonoprazan increased the time pH remained above 4 from baseline [85.5% (45–90.5)] to post-treatment [91.85% (80–90)] (p = 0.007). Compared with placebo, 1 mg/kg vonoprazan maintained pH above 4 for a significantly greater proportion of time (90.28 ± 5.6 vs. 5.68 ± 39; p = 0.021). Vonoprazan was well tolerated and effectively maintained intragastric pH above 4 at the 1 mg/kg dose in horses, supporting additional study of this drug as a potential alternative to omeprazole for EGUS management.