ABSTRACT Memory dysfunction refers to the deterioration of cognition that affects the ability to reason, remember, make decisions, and communicate. Strategic Acetylcholinesterase enzyme inhibition helps in combating age-related neuronal degeneration that leads to memory loss. Some Cissus species have been reported for memory-enhancing activity, but there is still a dearth of research for this genus. Hence, the memory-enhancing activity of Cissus arguta and Cissus quadrangularis will be assessed. The plant samples (leaves and stems) were air-dried, pulverised, extracted to obtain methanolic extracts, concentrated in vacuo, and the extracts were subjected to in vitro acetylcholinesterase inhibitory activity using a modified Ellman’s colorimetric assay method with eserine as the standard drug. The most active crude extract was then partitioned into n-hexane, dichloromethane, and methanol fractions and investigated for in vitro acetylcholinesterase inhibitory activity. All extracts had acetylcholinesterase inhibitory effect but the highest inhibition was observed in Cissus arguta leaf crude extract (IC50 = 0.23 ± 0.02 mg/mL), followed by Cissus quadrangularis stem extract (IC50 = 0.47 ± 0.02 mg/mL), Cissus quadrangularis leaf extract (IC50 = 0.85 ± 0.02 mg/mL) and Cissus arguta stem extract ((IC50 = 3.82 ± 0.23 mg/mL). The methanol fraction of Cissus arguta leaf extract showed promising acetylcholinesterase activity with an IC50 value of 0.06 ± 0.004 mg/mL. All values are comparable with the standard drug, eserine (IC50 = 0.04 ± 0.001 mg/mL). Cissus arguta and Cissus quadrangularis crude extracts possess memory-enhancing activity and are potential sources of drug candidates that can be harnessed in drug discovery to manage neurodegeneration and memory loss.