4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is a promising target for new herbicide research. To develop new HPPD-inhibiting herbicides, we used a scaffold-hopping strategy by introducing a quinazolinone ring and combining it with the classic triketone pharmacophore, designing and synthesizing a series of novel HPPD inhibitors with a fused-ring architecture. The results showed that II-series of compounds exhibited excellent inhibitory activity against Arabidopsis thaliana (At) HPPD, with IC50 values 0.5- to 2.5-fold lower than those of mesotrione. Moreover, we obtained the crystal structure of AtHPPD-II-36 complex at a resolution of 1.8 Å. Importantly, II-36 exhibited high safety to wheat and outstanding herbicidal efficacy against Echinochloa crus-galli, Digitaria sanguinalis, and Bromus japonicus at a dosage of 30 g ai/ha. Our study provides a valuable example for designing novel HPPD inhibitors with enhanced herbicidal activity and improved crop selectivity.