A simple, efficient, and highly promising approach for synthesizing poly-substituted quinolines derivatives has been developed using a CdO@ZrO₂ nanocomposite catalyst via the Knoevenagel–Michael reaction. This catalytic system offers several advantages, including easy preparation, cost-effectiveness, user-friendly handling, and remarkable stability. The nano-composite was synthesized from Cadmium nitrate and Zirconium oxide (ZrO₂) and was extensively characterized utilizing various instrumental techniques, such as BET, PXRD, SEM, TEM, and SEM–EDX analysis. Further, the structural elucidation of all synthesized target compounds was performed through advanced spectroscopic techniques, including ¹H-NMR, ¹⁵N-NMR, ¹³C-NMR, and HRMS. The proposed methodology offers a green and sustainable synthetic route for poly-substituted quinoline scaffolds, ensuring high yields (93–97%), exceptional selectivity, and mild reaction conditions. Notably, the reaction proceeds without requiring chromatographic purification, features significantly reduced reaction times, and allows for catalyst recovery and reuse for a minimum of seven consecutive cycles without considerable loss in product yield. This innovative approach aligns with green chemistry principles, promoting sustainability by minimizing waste generation, reducing energy consumption, and eliminating hazardous reagents. The method provides a viable and eco-friendly alternative to previously established synthetic protocols, contributing to the advancement of environmentally benign organic synthesis.