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Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer’s disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified <i>Xysmalobium undulaum</i> (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of <i>X. undulatum</i> were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (<b>1</b>), xysmalogenin-3, β-<span style="font-variant: small-caps;">d</span>-glucopyranoside (<b>2</b>), and crotoxigenin 3-<i>O</i>-glucopyranoside (<b>3</b>), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound <b>1</b>, a novel cardenolide, and <b>2</b> significantly decreased the Aβ42 levels in a dose-dependent manner while compound <b>3</b> was inactive. In silico investigations identified the AD’s β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.