Clostridium difficile infection (CDI), the occurrence has been increasing in the community as well as hospital-care facilities, resulting in higher morbidity and mortality rate. C. difficile, anaerobic pathogen greatly associated with antibiotic resistance and majorly linked to the irrational antibiotic use, which accelerate the alarming situation causing endemic as well epidemic globally. It is the budding menace and one of the major sources of nosocomial infection, i.e., hospital-acquired infection. The prevailing risk to public health by the antibiotics and their resistance majorly has driven the urge for utilizing the traditional herbal medicine into a sophisticated approach as a Modern/Ayurvedic Medicinal System (AMS). The current study aims to find out the promising herbals to combat the threat caused by C. difficile by applying herbal informatics as a holistic approach. Total 44 plants were elucidated against the virulence factors of the bacterium using the systematic bioprospection approach, out of which 5 plants were optimized that may be futher validated at the preclinical leve