The entitled review aimed to assemble and highlight the synthetic approaches and biological aspects of heterocycles with pyridodipyrimidine motifs. The recent synthetic approaches were categorized according to the accomplishments of the approaches under catalyst or catalyst-free conditions. The topic involved the synthesis of substituted tricyclic systems and spirocyclic systems. The present study offered an overview of the recent literature in addition to a scope of the preceding literature. The proposed mechanisms of the varied target products were discussed. Pyridodipyrimidine displayed potential and privileged cytotoxic, antioxidant, and antimicrobial performances. The competitions, challenges, and prospects are also deliberated.