[Objective] To investigate the effects of stress response and glucolipid metabolism in perioperative patients udergoing total knee replacement with ultrasound-guided lumbar plexus-sciatic nerve block. [Methods] 80 patients undergoing total knee arthroplasty in our hospital were selected and randomly divided into general anesthesia group (group C) and lumbar plexus-sciatic nerve block combined with general anesthesia group (group L) using the random number table method, with 40 patients in each group. The patients in Group C received general anesthesia, and the patients in group L received ultrasound-guided lumbar plexus-sciatic nerve block combined with general anesthesia. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting blood glucose (FPG), fasting insulin (FINS), cortisol (Cor) and prostaglin E2 (PGE2) during the perioperative period were compared between the two groups. Perioperative arrhythmia of lead II electrocardiogram and postoperative adverse reactions were recorded. [Results] Compared with the preoperation, TC, TG, HDL and LDL levels in the postoperation in the two groups decreased (P<0.05), and FPG, FINS, Cor and PGE2 levels increased (P<0.05). Compared with the group C in the postoperation, HDL levels increased in the group L (P<0.05), and TC, TG, LDL, FPG, FINS, Cor, PGE2 levels decreased (P<0.05).Compared with the group C, the incidence of intraoperative arrhythmia and postoperative adverse reactions in the group L decreased (P<0.05). [Conclusions] Ultrasound-guided lumbar plexus-sciatic nerve block could reduce perioperative stress response, improve perioperative glucolipid metabolism of patients undergoing total knee arthroplasty, reduce adverse reactions, and ensure the safety of patients.