Objective: Therapeutic hypothermia is an established neuroprotective strategy for hypoxic–ischemic brain damage (HIBD); however, nursing-led temperature control pathwaysand their effects on intestinal barrier function remain insufficiently defined. This study aimed to develop a targeted temperature management (TTM)–guided transrectal precision mild hypothermia nursing strategy and evaluate its mechanistic and clinical value from a gut–brain axis perspective. Methods: An integrated basic-to-clinical translational design was employed. Eighty male Sprague–Dawley rats were randomized into sham, normothermic HIBD, and transrectal mildhypothermia groups. HIBD was induced by bilateral common carotid artery ligation with hypoxic exposure. The hypothermia group received 12 hours of transrectal precision mild hypothermia using a selfdeveloped cooling device with continuous 4 °C isotonic saline perfusion, followed by spontaneous rewarming. Intestinal barrier integrity was assessed by histopathology , bacterial translocation, and serum diamine oxidase (DAO) and D-lactate levels. Clinically , 37 mechanically ventilated children with HIBD were prospectively enrolled and treated with TTM-based transrectal mild hypothermia nursing protocol, with continuous monitoring of temperature control and safety outcomes. Results: Transrectal mild hypothermia preserved intestinal mucosal integrity , reduced DAO and D-lactate levels (P < 0.05), and limited bacterial translocation in HIBD rats. Clinically , the mean cooling rate was 1.2 ± 0.8 °C/h, with stable temperature maintenance in 91.9% of measurements and controlled rewarming in 81.2% of patients. No malignant arrhythmias or refractory hypotension occurred. Conclusion: A TTM-guided transrectal precision mild hypothermia nursing strategy enables effective, stable, and safe temperature control while protecting intestinal barrier function in HIBD, representing a nursing-driven translational approach targeting the gut–brain axis.