The phenolic extract of Senecio biafrae leaves was investigated to determine the in vitro antioxidant, phenolic profiles, and inhibition of key enzymes relevant to type II diabetes mellitus (α‐amylase and α‐glucosidase) and Alzheimer's disease (acetylcholinesterase and butrylcholinesterase). The phenolic extract demonstrated significant scavenging abilities against all in vitro antioxidant parameters assessed. Reversed‐phase HPLC of the extract revealed the presence of gallic acid, chlorogenic, caffeic acid, rutin, quercetin, and kaempferol. The extract also inhibited activities of α‐amylase (IC₅₀ = 126.90 μg/ml), α‐glucosidase (IC₅₀ = 139.66 μg/ml), acetylcholinesterase (IC₅₀ = 347.22 μg/ml), and butrylcholinesterase (IC₅₀ = 378.79 μg/ml), which may be attributed to the antioxidant potential of the extract and its phenolic composition. Therefore, this study suggests that the leaves of S. biafrae may be useful in the management of diabetes mellitus and Alzheimer's disease.