Trazodone is a dose-dependent serotonin antagonist and agonist used to treat anxiety-related conditions. Trauma has been identified as the leading cause of morbidity and mortality in several nondomestic ruminant species and can be exacerbated by stress. In a recent study in domestic goats (Capra aegagrus hircus), trazodone reduced activity levels without adverse effects. Trazodone could allow for safer capture and handling in nondomestic ruminant species. The objectives of this study were to identify a dose of trazodone that decreases activity levels in captive blue wildebeest (Connochaetes taurinus) and to evaluate its safety and its effects on serum cortisol levels following a routine veterinary procedure. A pilot study using ethograms identified a group fed 15 mg/kg oral dose of trazodone as effective to reduce activity levels. Over 6 h, this dose resulted in a 111% increase in time spent sleeping or resting (P = 0.0003), a 41% increase in time spent lying down (P = 0.0016), a 64% reduction in time spent moving (P= 0.005), and a 65% reduction in time spent being vigilant (P= 0.026). Systemic absorption of trazodone was identified when plasma concentrations were measured after 2 h (95 ± 48 µg/L). Serum cortisol levels during a routine venipuncture event were not significantly different following trazodone administration (P > 0.05). Mild hyporexia was the only adverse effect noted at 15 mg/kg and was absent at a 12 mg/kg dose. Trazodone appears safe and promising to decrease activity in blue wildebeest and might thus have a positive effect on nondomestic ruminant welfare and the safety of veterinary procedures.