Persimmon (Diospyros kaki L.), a fruit rich in phenolic compounds (PCs), has been considered effective in mitigating oxidative damage induced by an excess of reactive oxygen species. Due to large molecular weight and intrinsic instability in some physiological fluids, PCs’ passage through biological membranes is very limited. Carriers like phytosomes are promising systems to optimize oral absorption of encapsulated extracts. This work prepared and fully characterized phytosomes containing bioactive phenolic extracts from persimmon in terms of size, surface charge, encapsulation efficiency and stability over six months. These phytosomes were orally dosed to Wistar rats during a 15-day period. Afterwards, haematological and biochemical analyses were performed. Monodisperse phytosomes were successfully prepared, with size less than 300nm (PI < 0.3) and high encapsulation efficiency (97.4%) of PCs. In contrast to free extract, extract-loaded phytosomes had higher antioxidant activity after 6 months storage. Oral administration of extract-loaded phytosomes and free extract did not lead to lipidic profile changes and were within referenced normal ranges, as well as glycaemia levels and urine parameters. The results highlighted the potential of persimmon PCs as food supplements or pharmacological tools, suggesting a promising and safe phytosomal formulation containing bioactive agents of persimmon that could lead to health benefits.