Candida albicans is a common opportunistic pathogen and normally resides in the human gut. Increasing number of reports link the overgrowth of C. albicans to the severity of ulcerative colitis (UC). Sodium houttuyfonate (SH), a derivative of the medicinal herb Houttuynia cordata Thunb, has been demonstrated to exhibit decent antifungal and anti-inflammatory activities. We showed previously that SH could ameliorate colitis mice infected with C. albicans. However, it is unclear whether the therapeutic effect of SH is connected to its modulation of intestinal microflora in UC. In this study, the impact of SH on the gut microbiota was explored in both cohabitation and non-cohabitation patterns. The results showed that in UC mice inflicted by C. albicans, the administration of SH could greatly improve the pathological signs, weaken the oxidative stress and inflammatory response, and enhance the intestinal mucosal integrity. By 16S rRNA gene sequencing, we found that C. albicans interference caused intestinal microbiota dysbiosis accompanied by an increase of some harmful pathogens including Klebsiella and Bacteroides. In contrast, SH could modulate the abundance and diversity of microbiota with an increase of several beneficial bacteria comprising short-chain fatty acid-producing bacteria (Lachnospiraceae_NK4A136_group, Intestinimonas) and probiotics (Lactobacillus and Alloprevotella). Furthermore, the cohabitation strategy could also prove the efficacy of SH, indicating a role of transmissible gut flora in the colitis model. These findings suggest that SH might be an effective compound for the treatment of UC complicated by C. albicans overgrowth through maintaining gut microbiota homeostasis, thereby improving intestinal function.