Background: In Shaanxi province, China, the aqueous extract of Rubia cordifolia's aerial part (AERCAP) is traditionally used to manage diarrhea. However, there is no scientific evidence to verify the safety and efficacy of its use. The aim of this study was to investigate the anti-diarrheal and anti-inflammatory effects of AERCAP by using a rodent model. Methods: The anti-diarrheal effects were studied by senna leaf-induced diarrheal and intestinal transit experiments in mice. The anti-inflammatory activity was investigated by trinitrobenzenesulfonic acid (TNBS)-induced colonic inflammation in rats. Results: The results indicated that AERCAP delayed the onset of semi-solid feces, reduced the evacuation index (EI) in senna leaf-induced diarrheal in mice, and inhibited the propulsive movement in castor oil-induced intestinal transit but not in the normal intestinal transit test. The results were compared with the standard anti-diarrheal drug loperamide. Additionally, oral treatment with AERCAP significantly decreased the macroscopic damage area, improved the microscopic structure, and reduced the malondialdehyde (MDA) content, IL-1 beta and TNF-alpha levels in colonic tissue compared with the TNBS control group in rats. Conclusions: AERCAP exhibited anti-diarrheal and anti-inflammatory activities in a rodent model. The study validated the traditional use of the plant in Chinese herbal medicine as a valuable natural remedy for the treatment of diarrhea.