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Background: Lodging seriously affects sugarcane stem growth and sugar accumulation, reduces sugarcane yield and sucrose content, and impedes mechanization. However, the molecular mechanisms underlying sugarcane lodging tolerance remain unclear. In this study, comprehensive transcriptomic and proteomic analyses were performed to explore the differential genetic regulatory mechanisms between upright (GT42) and lodged (GF98-296) sugarcane varieties. Results: The stain test showed that GT42 had more lignin and vascular bundles in the stem than GF98-296. The gene expression analysis revealed that the genes that were differentially expressed between the two varieties were mainly involved in the phenylpropanoid pathway at the growth stage. The protein expression analysis indicated that the proteins that were differentially expressed between the two varieties were related to the synthesis of secondary metabolites, the process of endocytosis, and the formation of aminoacyl-tRNA. Time-series analysis revealed variations in differential gene expression patterns between the two varieties, whereas significant protein expression trends in the two varieties were largely consistent, except for one profile. The expression of CYP84A, 4CL, and CAD from the key phenylpropanoid biosynthetic pathway was enhanced in GT42 at stage 2 but suppressed in GF98-296 at the growth stage. Furthermore, the expression of SDT1 in the nicotinate and nicotinamide metabolism was enhanced in GT42 cells but suppressed in GF98-296 cells at the growth stage. Conclusion: Our findings provide reference data for mining lodging tolerance-related genes that are expected to facilitate the selective breeding of sugarcane varieties with excellent lodging tolerance. [ABSTRACT FROM AUTHOR]