Copper nitrate hydroxide (CNH)-containing mesoporous silica nanoparticle (MSN) with g-C3N4 framework (MSN/C3N4/CNH) was fabricated via a four-step hydrothermal synthesis method. Functionalized MSN-based C3N4 was prepared, decorated with CNH, and identified by different physicochemical techniques such as FT-IR, XRD, SEM, EDX, and STA analyses. Then, MSN/C3N4/CNH composite was utilized as a robust catalyst for the fast fabrication of biologically active polyhydroquinoline derivatives with high yields between 88 and 97% via Hantzsch reaction under mild reaction conditions and short reaction time (within 15 min) owing to synergistic influence of Lewis acid and base sites. Moreover, MSN/C3N4/CNH can be straightforwardly recovered and used up to six reaction cycles without a conspicuous decrease in efficiency.