A simple, facile, and efficient green methodology has been developed for the synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives by the one-pot four-component reaction of cinnamaldehyde/crotonaldehyde, 2-hydroxy-1,4-naphthoquinone, 1,3-dimethyl-6-amino uracil, and o-phenylenediamine in ethanol medium under reflux conditions using p-TSA as a catalyst. In this environmentally benign methodology, three C-N and two C-C bonds are formed in one pot. The hybrid products have three bioactive moieties such as benzophenazine, tetrahydropyridine, and pyrimidine. Operational simplicity, metal-free conditions, wide substrate scope, readily available starting materials, moderate to good yields of the desired products, presence of pharmaceutically active moieties, and easy purification process are the notable features of this methodology. [GRAPHICS] .