Treatment ofClostridioides difficileinfection (CDI) is expensive and complex, with a high proportion of patients suffering infection relapse (20–35%), and some having multiple relapses. A healthy, unperturbed gut microbiome provides colonisation resistance against CDI through competition for nutrients and space. However, antibiotic consumption can disturb the gut microbiota (dysbiosis) resulting in the loss of colonisation resistance allowingC. difficileto colonise and establish infection. A unique feature ofC. difficileis the production of high concentrations of the antimicrobial compoundpara-cresol, which provides the bacterium with a competitive advantage over other bacteria found in the gut.p-cresol is produced by the conversion ofpara-Hydroxyphenylacetic acid (p-HPA) by the HpdBCA enzyme complex. In this study, we have identified several promising inhibitors of HpdBCA decarboxylase, which reducep-cresol production and renderC. difficileless able to compete with a gut dwellingEscherichia colistrain. We demonstrate that the lead compound, 4-Hydroxyphenylacetonitrile, reducedp-cresol production by 99.0 ± 0.4%, whereas 4-Hydroxyphenylacetamide, a previously identified inhibitor of HpdBCA decarboxylase, only reducedp-cresol production by 54.9 ± 13.5%. To interpret efficacy of these first-generation inhibitors, we undertook molecular docking studies that predict the binding mode for these compounds. Notably, the predicted binding energy correlated well with the experimentally determined level of inhibition, providing a molecular basis for the differences in efficacy between the compounds. This study has identified promisingp-cresol production inhibitors whose development could lead to beneficial therapeutics that help to restore colonisation resistance and therefore reduce the likelihood of CDI relapse.