Salt stress limits plant growth and agricultural productivity and plants have evolved suitable mechanisms to adapt to salinity environments. It is important to characterize genes involved in plant salt tolerance, which will advance our understanding of mechanisms mediating salt tolerance and help researchers design ways to improve crop performances under high salinity environments. Here, we reported a CYP450 family member, CYP75B4, improves salt tolerance of rice seedlings by inducing flavonoid tricin and cell wall lignin accumulation. The CYP75B4 is highly expressed in tissues rich in cell walls and induced by salt treatment. Subcellular localization analysis revealed that CYP75B4 is localized in the endoplasmic reticulum (ER). The CYP75B4 overexpressing (CYP75B4-OE) lines showed significant enhancement in stem mechanical strength, whereas the cyp75b4 null mutants displayed weaker stems, as compared to the wild-type. Notably, the cyp75b4 and CYP75B4-OE lines showed decreased and improved, respectively, salt tolerance performances in terms of survival rate, ROS accumulation, and Na