Background: Terminalia avicennioides is a medicinal plant used traditionally in Nigeria to treat numerous ailments and disorders which include coughs, purgative and emetic. Objective: This study scientifically evaluated the probable mechanism of the anti-emetic activity of methanol root extract of Terminalia avicennioides Guill. & Perr. on histaminergic and serotonergic receptors of isolated rabbit ileum. Methodology: Fresh root bark was extracted using methanol and the antiemetic effect was evaluated by experimenting on a small segment (3 cm) of isolated rabbit ileum, using the data capsule (Ugo Basile) and single chamber isolated tissue apparatus. Varying concentrations of histamine and serotonin (0.05, 0.1, 0.2, and 0.4 mg/ml) were used to obtain contractions as they act on histamine and serotonergic receptors respectively. Results: META (0.05 mg/ml, 0.1 mg/ml, 0.2 mg/ml, and 0.4 mg/ml) exhibited a significant concentration-dependent decrease at p<0.05 in histamine-induced and serotonin-induced contractions on isolated rabbit ileum from the data capsule reading with percentage inhibition of 43.22, 53.96, 75.35, 85.58 % and 21.62, 49.50, 78.67 and 86.96 % respectively for the different concentrations. Conclusion: The study showed that methanol root extract of Terminalia avicennioides acts on cholinergic (muscarinic), histaminergic, and serotonergic receptors of isolated rabbit ileum by inhibitory spasmolytic action against smooth muscle contractility, hence its ability to possess anti-emetic effect to relieve vomiting.