Abstract: Proso millet is a small-seeded grass crop that produces large amounts of grain. Proso millet is also usually cultivated in arid and semi-arid regions of China, due mainly to its drought resistance, barren tolerance, and early maturity. In proso millet fields, chemical herbicides are mostly used to remove or prevent the growth of unwanted plants, such as weeds, invasive species, or agricultural pests. However, the herbicides can inevitably damage the proso millet, even to cause phytotoxicity of crops in the weeding. As such, safeners can be added to reduce the damage of herbicides to plants. Nevertheless, there is still a lack of research concerning the effects of safeners and herbicides on the soil environment and root active oxygen metabolism of proso millet. Therefore, this study aims to explore the effects of safeners on the mitigation of herbicide damage, the soil enzyme activity, the root antioxidant enzyme activity, as well as the growth and development of proso millet. Taking proso millet variety’ Yumi-2’ as the material in Yulin, Shaanxi Province in 2019, four patterns of herbicides compounding were designed, including one pre-emergence herbicide: Guyou (10% monosulfuron wettablepowder, 2.4 kg/hm², H1), Guyou add brassins (300 mL/hm2, H1S1), Guyou add gibberellin (300 mL/hm2, H1S2), and Guyou add Naian (1.2 kg/hm2, H1S3), meanwhile, the tap water (CK1) and artificial weeding (CK2) as controls. Moreover, the chemical and physical parameters were determined, including the control effect of weed fresh weight, phytotoxicity index, rhizosphere soil enzyme activity, root antioxidant enzyme activity, Maleicdialdehyde (MDA) content, agronomic traits and yield. The results showed that: 1) The phytotoxicity indexes of brassins, gibberellin, and Naian combined with Guyou significantly decreased by 20.27%, 21.63%, and 20.94%, respectively, but there was no significant change in the weed control effect. 2) The soil invertase and urease activities in the H1 treatment were dramatically inhibited, compared with that in the CK1 at 7-42 days after spraying, where the activity inhibition rate decreased with the time. Furthermore, the activities of soil invertase and urease significantly increased, whereas, the inhibition rate was significantly reduced after adding the safener (H1S1, H1S2, and H1S3 treatments). It infers that the mixed spraying of safener and Guyou can reduce soil alkaline phosphatase and catalase activities. 3) The root Superoxide Dismutase (SOD) activity in the H1 treatment was significantly lower than that in the CK1 at 14-28 d, while that was higher than that in the CK1 at 42-70 d. The activity of root SOD in the safener compound was higher than that in the H1 treatment at 14-28 d after spraying, while that was lower than that in the H1 treatment at 42-70 d. The root Catalase (CAT) activity in the H1 treatment was higher than that in the CK1 at 14-42 d, while was lower than that in the CK1 at 70-96 d. The CAT activity was reduced in safener compound after spraying. The root MDA content in the H1 treatment increased significantly, while it decreased significantly in the safener compound treatment after spraying. 4) Monosulfuron-methyl resulted in the reduction of plant height in proso millet, ear length, and main ear weight. The combined application of safeners reduced the adverse effects of herbicides. The yield of each treatment was higher than that of CK1. The combination of monosulfuron-methyl and gibberellin yields the highest yield, reaching 5 035 kg/hm2, which is an increase of 1 114 kg/hm2 compared with CK1 treament and 1 061 kg/hm2 compared with H1 treament. The combination of safener and monosulfuron-methyl can delay the inhibition of monosulfuron-methyl on the rhizosphere soil enzyme activity of proso millet, while increase the activities of soil invertase and urease, as well as the root SOD activity. It infers that the combined addition can be used to reduce the membrane lipid peroxidation, the damage of cell membrane system, and the senescence process of root system, while to increase plant height, stem thickness, ear length, main ear weight, and yield of proso millet. The findings demonstrated that the combination of safener gibberellin and herbicide monosulfuron-methyl can have a better effect to alleviate the herbicide damage, while promote the yield of proso millet.