4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27; HPPD) represents a potential target for novel herbicide development. To discover the more promising HPPD inhibitor, we designed and synthesized a series of bis-5-cyclopropylisoxazole-4-carboxamides with different linkers using a multitarget pesticide design strategy. Among them, compounds and displayed excellent herbicidal activities versus () and () with the inhibition of about 90% at the concentration of 100 mg/L in vitro, which was better than that of isoxaflutole (IFT). Furthermore, compounds and displayed the best inhibitory effect versus and with the inhibition of about 90 and 85% at 90 g (ai)/ha in the greenhouse, respectively. The structure-activity relationship study showed that the flexible linker (6 carbon atoms) is responsible for increasing their herbicidal activity. The molecular docking analyses showed that compounds and could more closely bind to the active site of HPPD and thus exhibited a better inhibitory effect. Altogether, these results indicated that compounds and could be used as potential herbicide candidates targeting HPPD.