<p>Curcumin has attracted considerable interest as a natural medicine due to its diverse pharmacological activities. However, its high molecular flexibility presents a significant challenge for computational characterization. In this study, the conformational space of curcumin was systematically explored using an integrated computational workflow consisting of GFN2-xTB conformational sampling, CENSO-assisted conformer selection and refinement, K-means clustering, and subsequent final geometry optimization. Four different conformational search workflows were evaluated. Based on Boltzmann population analysis and computational efficiency, a workflow comprising conformational sampling, pre-screening, screening, clustering, and APFD/6–311 +  + G(d,p) optimization was selected for subsequent investigations. Using this workflow, the effects of solvent polarity on the conformational stability and electronic properties of curcumin were investigated in the gas phase, hexane, ethanol, dimethyl sulfoxide, and water. The results show that solvent environments significantly stabilize both keto and enol conformers relative to the gas phase, with stabilization generally increasing with solvent polarity. Solvent-dependent structural variations were observed, particularly in the orientation of the methoxy groups in the enol form and the bending of the diketone moiety in the keto form. Furthermore, the HOMO–LUMO energy gap decreases in solution relative to the gas phase, with the enol form consistently exhibiting smaller energy gaps than the keto form. Overall, this study provides molecular-level insights into the solvent-dependent conformational and electronic properties of curcumin and demonstrates the effectiveness of an integrated conformational search strategy for highly flexible molecules.</p>