Inflammatory bowel diseases (IBDs) are chronic, relapsing and multifactorial disorders of the colonic mucosa, which show increased and unbalanced intestinal immune response to external stimuli. Plant-derived extracts were described to possess the capability in contrasting IBDs-related oxidative stress and inflammatory pathways. In the present study, we investigated the water extract of Harpagophytum procumbens DC. ex Meisn. in an experimental model of IBD. Additionally, a microbiological investigation was carried out to discriminate the efficacy against bacterial and fungal strains involved in IBDs. An untargeted proteomic analysis was also conducted on more than 100 colon proteins involved in tissue morphology and metabolism. The extract showed the ability to blunt the level of selected biomarkers of oxidative stress and inflammation, including serotonin, prostaglandins, cytokines and transcription factors. Additionally, the extract inhibited the growth of Candida albicans and C. tropicalis, in vitro. The extract was also able to exert a pro-homeostatic effect on the levels of a wide plethora of colon proteins, thus corroborating protective effects against the burden of inflammation and oxidative stress. On the other hand, the supra-physiological downregulation of cytoskeletal-related proteins involved in tissue morphology and antimicrobial barrier function suggests caution in the use of food supplements enriched with H. procumbens.