Buddleja salviifolia leaves are used for the treatment of eye infections and neurodegenerative conditions in South Africa. Three phenolic compounds identified as 4′-hydroxyphenyl ethyl vanillate (1), acteoside (2) and quercetin (3) from leaf extracts of the B. salviifolia were investigated for cyclooxygenase-2 (COX-2) inhibition and antioxidant activities using β-carotene–linoleic acid and DPPH assays. In silico parameters were also determined for COX-2. All the compounds exhibited good inhibition activity against COX-2 and moderate antioxidant activities at a screening concentration of 25.0μg/ml. Acteoside was the most potent in all assays. It exhibited the lowest IC50 value (4.28μg/ml) in the COX-2 and EC50 values of 24.15 and 63.30μg/ml in the β-carotene–linoleic acid and DPPH assays respectively. Computational molecular docking showed its molecular interaction with important amino acid residues in the catalytic site of COX-2, revealing its potential binding mode at the molecular level. In silico study revealed that quercetin and acteoside showed the highest binding affinity (dock score of 92.18 and 68.93k.cal/mol) and good hydrogen bond interactions with active site residues. The activities demonstrated by these compounds (1–3) suggest that they could be useful in management of inflammatory conditions.