Cellulose nanocrystals possess unique properties such as high surface area and excellent biocompatibility. They can disrupt strong hydrogen bonds and other intermolecular forces that hinder the solubility of certain molecules thus enhancing the solubility of poorly soluble materials. The main challenge in formulating poorly soluble drugs lies in their limited therapeutic efficacy due to inadequate solubility and bioavailability. Therefore, an innovative approach such as using cellulose nanocrystals to enhance the solubility is highly needed. The aim of this research is to study the potential of ramie ( L. Gaud) as a source of cellulose nanocrystals in the development of microspheres for the solubility enhancement of poorly soluble drugs. Nanocrystalline cellulose was isolated from the ramie ( L. Gaud) by optimizing hydrolysis conditions with varying acid concentrations and reaction times. Characterizations were performed by measuring particle size, pH, and sulfate content, followed by morphological study by SEM, functional group analysis, and thermal analysis. The use of sulfuric acid in the hydrolysis process of flax cellulose at 45 °C, as the type of acid that gives the best results, at 50% acid concentration for 60 min produces cellulose nanocrystallines with a particle size of 120 nm, sulfate concentration density of 133.09 mmol/kg, crystallinity of 96.2%, and a yield of 63.24 ± 8.72%. Furosemide was used as the poorly soluble drug model and its solubility enhancement in the form of furosemide/RNCC microspheres was evaluated through saturated solubility testing and in vitro dissolution. This study demonstrated that RNCC could improve the solubility of furosemide, which contributes to developing sustainable drug formulations and eco-friendly delivery systems for poorly soluble drugs.