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Pterospartum tridendatum is an important source of active compounds with anti-inflammatory properties. The ability of P. tridentatum leaves methanolic extract in preventing/reversing inflammation was studied in adult rats using a model of experimental osteoarthritis (OA) and ear edema. Control animals (SHAM) were administered phosphate buffer solution (PBS), while OA animals received either P. tridentatum 100 mg/kg, 300 mg/kg, or a commercial anti-inflammatory (15 mg/Kg, Ibuprofen) via gavage, daily, for three weeks. Ear edema was induced, and the animals were divided into five groups treated with: (i) ethanol, (ii) P. tridentatum, (iii) croton oil, (iv) croton oil + P. tridentatum, and (v) croton oil + medrol. The inflammatory effect was evaluated by the measurement of the knee and ear edema. The chromatographic profile, evaluated by HPLC-DAD, showed numerous phenolic compounds are present. In the docking analysis of these compounds, isoquercetin demonstrated strong molecular interactions for peroxisome proliferator-activated receptor alpha and gamma (PPARα and PPARƴ, respectively), protein kinase 2 subunit α (CK2 α), and 5-lipoxygenase-activating proteins. Genistein had strong docking binding energies for CK2α and prostaglandin H (2) synthase-1. Our analysis showed the treatment with P. tridentatum extract reversed OA-induced edema in the rat knee, as well as ear edema, highlights this plant as a potential source of compounds that can be used as adjuvants in the management of inflammation.