Abstract: Rice sheath blight is one of the major diseases threatening rice production in China. This study employed pot experiments to systematically investigate the effects of seed treatment with thifluzamide and medium dosage lanthanum oxide seed treatment (Thf + LaO-M) on thifluzamide uptake, key enzyme activities, disease resistance, and physiological metabolism in rice, aiming to uncover its synergistic mechanism. Results indicate that lanthanum oxide treatment significantly enhances rice thifluzamide uptake, outperforming nano-lanthanum oxide and lanthanum nitrate. Compared to thifluzamide seed treatment alone (Thf), Thf + LaO-M treatment significantly enhanced the activities of superoxide dismutase (SOD), peroxidase (POD), polyphenol oxidase (PPO), catalase (CAT), and phenylalanine ammonia-lyase (PAL) in rice plants while reducing malondialdehyde (MDA) content. This mitigates oxidative damage and enhances plant disease resistance. The microchamber artificial inoculation test at the seedling stage confirmed that the relative disease rating of rice sheath blight in Thf + LaO-M treated group was significantly lower than that in Thf treated group. Metabolomic analysis revealed that Thf + LaO-M treatment significantly induced the accumulation of defense-related metabolites such as flavonoids, terpenoids, and phenolic acids. In summary, seed treatment with a mixture of lanthanum oxide and thifluzamide synergistically enhances control efficacy against rice sheath blight by promoting thifluzamide uptake, regulating antioxidant and defense enzyme activities, and modulating secondary metabolic pathways. These findings hold significant implications for improving fungicide utilization efficiency and disease control outcomes in seed treatment strategies.