Nucleoside hydrolases are a strategic target for the development of drugs to treat leishmaniasis, a neglected disease that affects 700 thousand to one million people annually. The present study aimed to identify <i>Leishmania donovani</i> nucleoside hydrolase (<i>Ld</i>NH) inhibitors from the leaves of <i>Ormosia arborea</i>, a tree endemic to Brazilian ecosystems, through a strategy based on <sup>1</sup>H NMR analyses and chemometrics. The aqueous EtOH extract of <i>O. arborea</i> leaves inhibited <i>Ld</i>NH activity by 95%. The extract was fractionated in triplicate (13 in each step, making a total of 39 fractions). Partial least squares discriminant analysis (PLS-DA) was used to correlate the <sup>1</sup>H NMR spectra of the fractions with their <i>Ld</i>NH inhibitory activity and thus to identify the spectral regions associated with the bioactivity. The strategy aimed at isolating the probable bioactive substances and led to two new A-type proanthocyanidins, linked to a <i>p</i>-coumaroyl unit (<b>1</b> and <b>2</b>), which appeared as noncompetitive inhibitors of <i>Ld</i>NH (IC<sub>50</sub>: 28.2 ± 3.0 μM and 25.6 ± 4.1 μM, respectively). This study confirms the usefulness of the NMR-based chemometric methods to accelerate the discovery of drugs from natural products.