Abstract: Ralstonia solanacearum, a major soil-borne bacterial disease, severely restricts tobacco production. The main cultivated varieties in Yunnan Province, Honghuadajinyuan and Yunyan 87 are closely related, but Yunyan 87 exhibits significantly stronger resistance to R. solanacearum than Honghuadajinyuan. However, the molecular mechanisms underlying this resistance difference remain unclear. In this study, we analyzed differentially expressed genes (DEGs) and rhizosphere bacterial community composition in both varieties after R. solanacearum infection, aiming to elucidate the molecular basis of their resistance differences by exploring correlations between cell wall-related genes and key bacterial taxa. The results showed that at 10 days post-inoculation (dpi), 9,024 and 11,237 DEGs were upregulated in Honghuadajinyuan and Yunyan 87, respectively; at 20 dpi, 3,959 and 4,262 DEGs were upregulated in the two varieties. Among the significantly upregulated DEGs, 112 were associated with cell wall synthesis and remodeling, including Pectin methylesterases (PMEs), Expansins (EXPs), and Xyloglucan endotransglucosylase/hydrolases (XTHs). Notably, the expression levels of these genes were significantly higher in Yunyan 87 than in Honghuadajinyuan after infection. Furthermore, the expression abundance of these three cell wall-related gene categories was significantly correlated with the enrichment of key bacterial genera, such as Pseudomonas, Acinetobacter, Castellaniella, Chryseobacterium, Enterobacter, and Bacillus. In conclusion, tobacco varieties may enhance resistance to R. solanacearum by specifically upregulating cell wall synthesis/remodeling genes and enriching beneficial bacterial taxa. Our findings suggest that cell wall-related genes play a critical role in tobacco defense against R. solanacearum.