TaohongSiwu decoction (THSWD), a traditional Chinese recipe, has been widely used to treat hypertension since ancient times. However, the mechanisms of its action are still unclear. Herein, we aimed to explore the gut microbial activity of THSWD in high-salt diet-induced hypertensive mice. Eight percent high-salt (NaCl) diet was used to induce hypertension for 4 weeks in a mouse model. Meanwhile, THSWD was used to intervene in the high-salt diet-induced mice, and the efficacy was evaluated by different parameters. Here, we found that THSWD significantly restored blood pressure compared with the model group. Moreover, THSWD effectively protected endothelial function by significantly upregulating the level of nitric oxide (NO) and downregulating the level of endothelin-1 (ET-1), angiotensin I (AngI), and vascular endothelial growth factor (VEGF) in serum compared with the model group. Notably, THSWD significantly upregulated the relative abundance of Dubosiella and downregulated that of Cyanobium_PCC-6307 and DNF00809 at the genus level compared with the model group. The results of PCA and microbial distance calculation further exhibited that THSWD treatment resulted in significant regulation of the microbial community. Furthermore, compared with the model group, THSWD increased the level of vitamin k2 (VK2) in serum. These findings indicate that THSWD could protect blood pressure and endothelial function by regulating gut microbiota and promoting microbial metabolite VK2. These results show the important role of THSWD in regulating the gut microbiota in response to high-salt diet-induced mice.