Clostridioides difficile infection is one of the leading causes of antibiotic-associated infectious diarrhea, and is associated with increased incidence and severity worldwide. While antibiotics have traditionally been used for prophylaxis and treatment of C. difficile infection, elevated antibiotic resistance has promoted the development and spread of C. difficile infection. Since the current standard-of-care antibiotics are ineffective for treating infections, there is an urgent need for novel antibacterial drugs or strategies to target C. difficile infection. C. difficile virulence and vital physiological functions are considered to be ideal targets. Thus, several promising lead compounds have been identified through screening both synthetic and natural product libraries. The goal of this review is to provide an update of the current scientific knowledge of C. difficile infection, focusing on small molecule inhibitors, which can effectively inhibit C. difficile by suppressing virulence or destroying vital physiological structures.