This review describes the current understanding of Clostridium (Clostridioides) difficile infection (CDI) in southeast Asia regarding the prevalence of CDI, C. difficile detection methods, antimicrobial susceptibility profiles, and the potential significance of a One Health approach to prevention and control. Our initial focus had been the Indochina region, however, due to limited studies/surveillance of CDI in Indochina, other studies in southeast Asian countries and neighboring Chinese provinces are presented here for comparison. Clostridium (Clostridioides) difficile infection is one of the most common causes of hospital-acquired gastroenteritis worldwide. Since its discovery as a cause of pseudomembranous colitis in 1978, C. difficile-related disease has been more prevalent in high-income rather than low-income countries. This may be because of a lack of knowledge and awareness about the significance of C. difficile and CDI, resulting in underreporting of true rates. Moreover, the abuse of antimicrobials and paucity of education regarding appropriate usage remain important driving factors in the evolution of CDI worldwide. The combination of underreporting of true CDI rates, along with continued misuse of antimicrobial agents, poses an alarming threat for regions like Indochina. C. difficile ribotype (RT) 027 has caused outbreaks in North America and European countries, however, C. difficile RT 017 commonly occurs in Asia. Toxin A-negative/toxin B-positive (A-B+) strains of RT 017 have circulated widely and caused outbreaks throughout the world and, in southeast Asia, this strain is endemic.