A sustainable and efficient protocol has been developed for the synthesis of polyhydroquinoline derivatives via a one-pot four-component Hantzsch reaction using copper nanoparticle-supported clinoptilolite (Cu NPs/clinoptilolite) as a heterogeneous catalyst. The catalyst was prepared by immobilizing copper nanoparticles onto natural clinoptilolite zeolite, providing high surface area, excellent metal dispersion, and enhanced catalytic activity. Various substituted aldehydes, dimedone, ethyl acetoacetate, and ammonium acetate underwent smooth condensation under optimized reaction conditions to afford the corresponding polyhydroquinoline derivatives in excellent yields with short reaction times. The Cu NPs/clinoptilolite catalyst exhibited remarkable stability, easy recovery, and reusability over successive reaction cycles without significant loss of activity. The enhanced performance is attributed to the synergistic effect between copper nanoparticles and the porous clinoptilolite framework, which facilitates efficient adsorption and activation of reactants. This environmentally benign catalytic system offers a simple, cost-effective, and green approach for the synthesis of biologically important polyhydroquinoline derivatives with potential pharmaceutical applications.