Background <p><i>Momordica balsamina</i> leaves are widely consumed for their nutritional and therapeutic properties. This study evaluated the effect of cooking and granulometric fractionation of <i>M. balsamina</i> leaf powders on their extractable bioactive compound content, antioxidant activities, and anti-hyperlipidemic properties.</p> Methods <p>Leaves were divided into raw and cooked batches, dried, ground, and fractionated into four granulometric classes: ≤50&#xa0;μm, 50–125&#xa0;μm, 125–200&#xa0;μm, and &gt; 200&#xa0;μm. In addition, unsieved crude powder ground at 1&#xa0;mm was kept as control and designated as PNT. The contents of total phenolic compounds, flavonoids, and condensed tannins were determined, and antioxidant activity was evaluated in vitro while in vivo hypolipidemic and antioxidant properties were studied in hyperlipidemic <i>Wistar</i> rats, with analysis of lipid parameters, transaminases, and oxidative stress markers.</p> Results <p>Cooking influenced the extractable/measurable bioactive compound content of the powder fractions, with the 50–125&#xa0;μm fraction of cooked leaves (D2) showing the highest content, and best antioxidant and hypolipidemic activities compared to PNT. D2 reduced total cholesterol (53.28%), triglycerides (48.72%), and LDL-c (86.35%), while increasing HDL-c by 194%. Hepatic parameters and oxidative markers showed a trend towards normalization, suggesting a hepatoprotective and antioxidant effect. Hypolipidemic and antioxidant activities were correlated with polyphenol, flavonoid, and tannin content.</p> Conclusion <p>Cooking and fractionation into four granulometric fractions plus PNT control enhanced extractable antioxidant and hypolipidemic properties of M. balsamina powder fractions in a rat model. As findings are based on preclinical data, further human studies are needed before any health applications can be considered.</p> Clinical trial number <p>Not applicable.</p>