Houttuynia drugs, including sodium houttuyfonate (SH) and sodium new houttuyfonate (SNH), are derivatives of the active ingredient of Houttuynia cordata, which can be used as both a vegetable and medicine in China. We aimed to explore the regulation effects of SH and SNH on the gut microbiota and production of inflammatory factors in mice. Here, we found that SH and SNH led to an increase in the production of interferon gamma and nuclear factor κ, and decreased the production of lipocalin-2 in the mice. The alpha diversity results of gut microbiota of the mice showed that the gut microbiota of the SH, SNH, and azithromycin treatment groups were significantly different from the control group, but the effects of reduced abundance and diversity of the SH and SNH groups were relatively lower than that of the azithromycin group. The beta diversity results indicated that the samples of each group were significantly grouped, and distribution of SH and SNH groups was more similar to the control group than the azithromycin group. Furthermore, SH and SNH groups had significant differences in the abundance of specific bacteria such as Escherichia–Shigella and Odoribacter, which might be associated with the increase of inflammatory factors. Therefore, our results suggested that SH and SNH may significantly affect the gut microbiota and production of inflammatory factors in the mice.