ABSTRACT Acanthospermum hispidum (AH) leaves have been widely used in traditional medicine for inflammation. In this study, the anti‐inflammatory effect of AH was evaluated, and a possible mechanism was predicted using an in silico model. The in vivo anti‐inflammatory activity of the AH extract was carried out using carrageenan, histamine and serotonin‐induced rat paw oedema, whereas molecular docking was used against all receptors implicated with inflammation. AH extract showed significant ( p < 0.01) inhibition at 50, 100, 150 and 200 mg/kg with all the models used ( p ˂ 0.05 to ˂0.0001) with a non‐significant decrease at T180; there were significances at some dose levels (e.g., 150 and 200 mg/kg). The peak percentage inhibition of the extract occurred at a dose of 100 mg/kg. A dose‐dependent increase in anti‐inflammatory activity was noted across the time examined T30—T150 with a non‐significant decrease at T180. F1 was found to be the most active fraction. However, stigmasterol showed a potent antagonist influence on COX‐1, COX‐II, CAT and INF‐gamma by showing binding affinities of −8.9, −8.9, −8.8 and −8.4 kcal/mol, respectively. Moreover, alkyl, carbon‐hydrogen, conventional hydrogen and van der Waals interactions were noted. Stigmasterol was observed to obey the Lipinski rule of five except MLOGP. These findings justify the ethnomedicinal information of the usage of AH in the management of inflammation and related ailments.