History A 4‐year old, 500 kg Thoroughbred female horse diagnosed with bilateral forelimb laminitis and cellulitis on the left forelimb became severely painful and refractory to non‐steroidal anti‐inflammatory therapy (flunixin meglumine on days 1, 2, 3 and 4; and phenylbutazone on days 5, 6 and 7) alone or in combination with gabapentin (days 6 and 7). Physical examination Pain scores assessed independently by three individuals with a visual analog scale (VAS; 0 = no pain and 10 = worst possible pain) were 8.5 on day 6, and it increased to 9.5 on day 7. Non‐invasive blood pressure monitoring revealed severe hypertension. Management As euthanasia was being considered for humane reasons, a decision was made to add an experimental new drug, trans‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid (t‐TUCB), which is a soluble epoxide hydrolase (sEH) inhibitor, to the treatment protocol. Dose and frequency of administration were selected based on the drug potency against equine sEH to produce plasma concentrations within the range of 30 nmol L?1 and 2.5 μmol L?1. Pain scores decreased sharply and remarkably following t‐TUCB administration and blood pressure progressively decreased to physiologic normal values. Plasma concentrations of t‐TUCB, measured daily, were within the expected range, whereas phenylbutazone and gabapentin plasma levels were below the suggested efficacious concentrations. Follow up No adverse effects were detected on clinical and laboratory examinations during and after t‐TUCB administration. No new episodes of laminitis have been noted up to the time of writing (120 days following treatment). Conclusions Inhibition of sEH with t‐TUCB was associated with a significant improvement in pain scores in one horse with laminitis whose pain was refractory to the standard of care therapy. No adverse effects were noticed. Future studies evaluating the analgesic and protective effects of these compounds in painful inflammatory diseases in animals are warranted.