Extreme environments in aerial, terrestrial, oceanic, and space conditions pose significant threats to human health and safety by damaging critical tissues and organs, thereby limiting the progress of human exploration. The immune system is distributed throughout various tissues and organs within human body, and interacts with other tissue-specific cells or cell communities, to form an extensive three-dimensional structure and a complex regulatory network. Through these interactions, the immune system maintains immune homeostasis and orchestrates the tissue injury recovery processes. Under extreme environmental stress, various stress factors are sensed, and transmitted, either directly or indirectly, into different tissues and organs of the body, ultimately affecting the cellular mechanical microenvironment. These biomechanical cues further reshaping immune cells by altering their structure and modulating their function through distinct mechanotransduction signaling pathways and regulatory networks, ultimately disrupting overall immune homeostasis as well as the injury recovery capacity. Therefore, investigating the immune injury processes induced by extreme environments is crucial for understanding the patterns of human damage and underlying the mechanobiological mechanisms of immune recovery. To further deepen understanding of the injury patterns to the human immune system in extreme environments, and clarify the mechanisms of extreme environmental factors on immune responses, this review summarizes the latest advances on immune damage caused by extreme environments. It introduces various ground-based simulation experimental methods for extreme environments, clarifies the impact of these environments on the immune system, and outlines the mechanobiological mechanisms by which the immune system perceives and responds to these stimuli. This review aims to provide a theoretical foundation for future research on extreme environment exploration and resource utilization.