Cholinesterase (ChE) inhibitors are used for the symptomatic treatment of Alzheimer’s disease and other neurological pathologies. There is interest in developing new ChE inhibitors from natural plant compounds. Water-soluble palm fruit extract (WSPFE) recovered from the aqueous oil palm vegetation liquor is rich in phenolic acids and has potential neuroprotective effects. Here, we investigated the effects of WSPFE samples on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). WSPFE ethyl acetate fraction (EAF) inhibited these enzymes the most (AChE IC50: 0.218 ± 0.029 μg ml^–1; BChE IC50: 222.860 ± 5.777 μg ml^–1) and had the highest AChE selectivity index (SI) value (1022.294) compared to whole samples and seven individual fractions but these effects were weaker than those of the AChE selective agent donepezil hydrochloride (DH) (AChE IC50: 0.013 ± 0.001 μg ml^–1; BChE IC50: 19.820 ± 1.415 μg ml^–1; AChE SI: 1524.615). Fractions containing p-hydroxybenzoic acid and protocatechuic acid had the lowest AChE SI values (7.584 and 9.367 respectively) and may thus, function as dual ChE inhibitors. Binary mixtures of DH and WSPFE EAF might have more potent inhibitory effects against these enzymes, as well as higher BChE/AChE selectivity. Further studies to investigate the ChE inhibition potential of these WSPFE samples are warranted.