This study aimed to evaluate the effects of high respiratory effort(HRE) on spleen, kidney, intestine, and peripheral perfusion in patients with respiratory failure during mechanical ventilation. HRE was defined as a pressure muscle index (PMI) > 6 cmH2O and airway pressure swing during occlusion (ΔPOCC) > 10 cmH2O. Capillary refill time(CRT) and peripheral perfusion index (PPI) were determined when HRE occurred. The resistance indices of the snuffbox, intestine, spleen, and kidney were measured using Doppler ultrasonography simultaneously. These parameters were re-measured when the patients had normal respiratory effort (NRE) following sedation and analgesia. A total of 33 critically ill patients were enrolled in this prospective observational study. There was a significant increase in CRT (p = 0.0345) and PPI (p < 0.0001) from HRE to NRE; meanwhile, the resistance index of the snuffbox artery decreased (p < 0.0001). Regarding splanchnic perfusion indicators, all resistance indices of the superior mesenteric artery (p = 0.0002), spleen (p < 0.0001), and kidney (p < 0.0001) decreased significantly when the patient changed from HRE status to NRE. HRE could decrease perfusion of peripheral tissues and splanchnic organs. The status of HRE should be avoided to protect splanchnic and peripheral organs in mechanically ventilated patients.