Aeromonas hydrophila is a freshwater-dwelling zoonotic bacterium that has economic importance in aquaculture. In the past decade, Aeromonas hydrophila has become increasingly important because of its emergence as a food-borne zoonotic pathogen that is resistant to different treatment regimes. Being an aquatic bacterium, Aeromonas hydrophila is frequently subjected to several stressful environmental conditions, including changes in temperature, acidic pH and starvation that challenge its survival. To cope with these stressful conditions, like every cell, A. hydrophila possesses stress response mechanisms, such as alternative sigma factors, two-component systems, heat shock proteins, cold shock proteins, and acid tolerance response systems that eventually lead the fittest to survive. Moreover, the establishment of genetic variations among the strains related to environmental stress is also of great concern. This review presents the understandings based on inter-strain variations and stress response behavior of A. hydrophila that are important to control the increasing outbreaks of this bacterium in both human populations and aquaculture.