To address the challenges associated with the crystallization tendency of natural bioactive drugs, we propose a strategy for encapsulating a model hydrophobic medicine, Nobiletin (NOB), using the self-assembly system formed by a peptide amphiphile C16-KVK-CONH2 (KVK). The experimental results demonstrate that at low concentrations, KVK forms micelles that can effectively encapsulate NOB molecules and significantly inhibit their crystallization. As the concentration increases, KVK self-assembles into a fibrous hydrogel, further enhancing the inhibition of NOB crystallization. In vitro release experiments reveal that NOB encapsulated by KVK exhibits superior release performance. When compared to traditional surfactants, KVK demonstrates better inhibitory effects on NOB crystallization, maintaining stability over a prolonged period, indicating its potential for hydrophobic drug delivery applications.