<p>Fatliquors are essential wet chemicals in the leather-making process, enhancing softness, suppleness, and durability by preventing fibril aggregation and filling voids. However, some fatliquors can also promote fungal growth on finished leather products. This study explores the potential of fatliquor produced via a green route from <i>Azadirachta indica</i> (Neem) seed oil. Neem, a tropical and subtropical tree native to India and Southeast Asia, is renowned for its medicinal properties, earning the moniker “village pharmacy” due to its antiseptic, antimicrobial, anti-inflammatory, anti-ulcer, anti-malarial, and anticancer benefits. In this research, fatliquor was synthesized from Neem seed oil through sulphation and applied for fatliquoring of leather. This leather was compared with commercially fatliquored leather, showing enhanced lubricity and mechanical properties. Furthermore, the high unsaturation level and significant antifungal properties of the Neem-based fatliquor resulted in the development of a novel, eco-friendly fatliquor for leather application.</p> Graphical abstract <p></p>