Despite its excellent anti-cancer capacity in green tea extract (GTE), its applications are constrained by its low bioavailability solubility and poor bioavailability. This study aimed to design and introduce a new, stable plasma, pH-sensitive niosomal (Nio) formulation of GTE using a thin-film hydration process. Instead of cholesterol, cholesterol hemisuccinate (CHEMS) was added to generate pH-sensitivity properties and, using polyethylene glycol (PEG) (Nio / GTE / PEG / CHEMS), pH-sensitivity and plasma stability properties were integrated simultaneously into one delivery device. GC/MS, UV-vis, DLS, optical microscopy, SEM, and TEM techniques were used for the characterization of formulations. The release of formulations with pH-sensitivity was assessed in vitro in two different buffers (pH 5 and 7.4). In vitro pH-sensitivity cytotoxicity experiment was done on three different MCF-7, HepG2, and HL-60 cancer cell lines and one normal cell line (hGF) to guarantee specificity against cancer cells in the formulation. The GTE's mass assay with GC shows many anticancer polyphenols are in the sample. The pH-responsive formulation provided positive advantages, including pH-sensitive sustainedrelease (about 77 percent after 24 h at pH 5) followed Higuchi release kinetics, smooth morphology of the globular surface, high trapping efficiency (81 percent), nanometer diameter (240 nm), and high stability after 3 weeks. Exposure of cancer cells to Nio / GTE / PEG / CHEMS has demonstrated excellent performance against MCF-7, HepG2, and HL-60 cell lines by strong cell internalization and synergistic toxic effect (> 50 percent; compared to free GTE). Interestingly, when treated with the formulations, the viability percentage of the normal cell line (hGF) was higher than the cancer cells, which suggests the higher formulation selectivity against cancer cells. Stable plasma, pH-sensitive niosomes will improve bioavailability and strengthen GTE's cytotoxic effect.