Ginger (Zingiber officinale) essential oil (GEO) was loaded into nanoliposome (NLP) for smart release in simulated in-vitro digestion. Optimal conditions for the fabrication of NLp-GEO were determined according to physical stability, size distribution and particle size. Morphological analyses (atomic force microscopy (AFM) and scanning electron microscopy (SEM)) confirmed the results of the dynamic light scattering (DLS). Structural evaluation (differential Scanning Calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR)) demonstrated the interaction between GEO and NLP. Additionally, the approximate size and loading capacity of optimized NLp-GEO (100 nm) was 100 nm and 66.24%. NLp-GEO release under oral, gastric, and intestinal conditions showed that over 90% of the nutraceutical was released after exposure to model gastrointestinal conditions. Finally, NLp-GEO structure showed an improved antioxidant, UV stability and reduced cytotoxicity on cell lines (human colon cancer (HT-29) and normal human umbilical vein endothelial cells (HUVEC). As an innovative smart sustained-release system in simulated in-vitro digestion, NLP-GEO would be a potential practical option in the food and pharmaceutical industries.