Drug nano-carriers are crucial for achieving targeted treatment against cancer disorders with minimal side effects. In this study, a pH-responsive nanocomposite based on halloysite nanotube (HNT) coated with carboxymethyl cellulose (CMC)/polyethylene glycol (PEG) hydrogel for controlled delivery of 5-Fluorouracil (5-FU), a hydrophobic chemotherapy drug prescribed for different types of cancers was synthesized for the first time using the water-in-oil-in-water (W/O/W) technique. The developed CMC/PEG/HNT/5-FU nanocomposite was characterized by dynamic light scattering (DLS), zeta potential, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Field emission scanning electron microscope (FE-SEM) to get information about the particle size, surface charge, interactions between functional groups, crystalline structure and morphology, respectively. High efficiencies in terms of drug entrapment and loading (46 % and 87 %, respectively) were attained. In-vitro drug release results revealed an improved and sustained 5-FU delivery in an acid environment compared to the physiological medium, corroborating the pH-sensitivity of the developed nano-carrier. Flow cytometry and MTT assays demonstrated that the 5-FU loaded nanocomposite had considerable cytotoxicity on MCF-7 breast cancer cells while it is not toxic against L929 fibroblast cells. The nanocomposite synthesized herein could serve as a platform for the pH-sensitive release of anti-cancer drugs.