This work presents a facile, metal-free, and atom-economical synthesis of pyrimido[2,1-a:4,3-a']diisoquinolines via an acid-promoted formal [2 + 2 + 1 + 1] annulation of readily available 1,2,3,4-tetrahydroisoquinoline and arylglyoxal monohydrates. This annulation proceeds through an azomethine ylide intermediate, achieving the direct N-H/α-C(sp3)-H difunctionalization of 1,2,3,4-tetrahydroisoquinolines and concurrent formation of multiple C-C and C-N bonds. The resulting polycyclic scaffolds are readily transformed into multifunctional photoluminescent materials that display aggregation-induced delayed fluorescence (AIDF) emission. Preliminary biological evaluation revealed that several derivatives potently inhibit key inflammatory mediators in lipopolysaccharide-activated macrophages, indicating their potential as promising anti-inflammatory lead candidates.