Abstract: High herbicidal efficacy and a low risk of resistance have made 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors an important focus in herbicide discovery. In this study, based on an active substructure splicing strategy, a series of 21 novel 2-trifluoromethyl oxadiazole nicotinamide derivatives (6, 7a-7t) were designed and synthesized. Their structures were fully characterized by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). Enzyme inhibition assays against AtHPPD revealed that several compounds, including 7a (IC₅₀ = 0.362 μmol/L), 7s (IC₅₀ = 0.221 μmol/L), and 7t (IC₅₀ = 0.117 μmol/L), exhibited inhibitory activities comparable to or better than the commercial herbicide mesotrione (IC₅₀ = 0.363 μmol/L). Molecular docking simulations were further conducted to rationalize the observed differences in inhibitory activity. Greenhouse herbicidal assays demonstrated that most compounds showed inhibitory effects against the tested weeds. Among them, the methylsulfonyl-substituted compound 7h and the ethylurea-substituted compound 7n exhibited the most promising herbicidal efficacy. At an application rate of 150 g a.i./hm², both compounds provided over 80% control against Echinochloa crus-galli, Setaria viridis, Digitaria sanguinalis, Amaranthus retroflexus, Chenopodium album, and Abutilon theophrasti, with particularly superior activity against Setaria viridis compared to mesotrione. Meanwhile, compounds 7h and 7n displayed good crop safety toward maize, wheat, and foxtail millet.These results suggest that the oxadiazole nicotinamide scaffold represents a promising lead structure for herbicide development, and compounds 7h and 7n may serve as potential candidates for the development of next-generation HPPD-inhibiting herbicides.