The leaves of African pumpkins (Momordica balsamina L.) are a commonly consumed traditional vegetable. They are a good source of polyphenolic antioxidants and carotenoids, which are, however, affected by cooking or digestion. We investigated the effect of household cooking methods (stir-frying or boiling) on the changes in bioactive metabolites, antioxidant capacity, release and accessibility of β-carotene and also inhibition of inhibitory activity against α-amylase and α-glucosidase enzymes during in vitro digestion of African pumpkin leaves compared to the raw leaves. Compared to boiled or raw leaves, stir-frying improved the availability of bioactive metabolites at the gastrointestinal phase. Quercetin 3-galactoside and rhamnetin 3-O-glucoside (marker compounds) discriminated the stir-fried leaves from raw leaves and boiled leaves after digestion. Stir-frying improved the release and accessibility of β-carotene and enhanced the antioxidant activities compared to boiling. Dialysable fractions of stir-fried leaves exhibited the greatest inhibitory activity against α-amylase and α-glucosidase enzymes compared to the raw and boiled leaves, as well as acarbose. Stir-frying, therefore, is recommended for use in household cooking to benefit consumers by increasing the intake of phenolics and β-carotene.