The sit-and-wait hypothesis predicts that bacterial durability in the external environment is positively correlated with the evolution of bacterial virulence. Many bacterial pathogens have been recognized as potential sit-and-wait pathogens due to their long-term environmental survival (high durability) and high host mortality (high virulence) such as Acinetobacter baumannii, Burkholderia pseudomallei, and Mycobacterium tuberculosis, etc. Shigella flexneri is a leading etiologic agent of diarrhea with high infection rates, severe consequences, and long-term environmental survival, which has multiple transmission routes like contaminated food (food-borne route), insanitary water (water-borne route) and direct person-to-person contacts, etc. These features make Shigella flexneri an ideal candidate of sit-and-wait bacterial pathogens. However, there is currently a lack of evidence to support the claim. In this study, we examine the potential of S. flexneri as a sit-and-wait pathogen via comparative genomic analysis, which reveals the unique features of Shigella flexneri in abiotic stress resistance, energy metabolism, and virulence factors, and confirms that S. flexneri is a highly potential sit-and-wait bacterial pathogen.