Background: Sepsis is one of the most common critical illnesses in intensive care unit (ICU) clinical practice. Intravenous infusion technology is an important method for life support. The commonly used deep vein indwelling is expensive, and the incidence of infection due to long-term placement is high. Ultrasound technology can guide clinical puncture operations in real time and greatly improve the success rate of puncture. In the present study, we aimed to explore the effect of ultrasound-guided external jugular vein puncture and catheterization in patients with sepsis.Methods: From December 2018 to December 2019, a total of 61 patients with sepsis from the ICU or neurology care unit (NCU) were included in the present study and were randomly divided into the experimental group (n=30) and control group (n=31). Ultrasound-guided indwelling cannula needle was used in the experimental group, and blind indwelling cannula needle was used in the control group. The success rate of puncture at first operation, indwelling complications (e.g., bleeding, redness, infection, poor infusion), and operation time of the 2 methods were compared.Results: A comparison of the patients in the control group with the experimental group indicated no significant differences in age, body mass index, sex, temperature, mean aortic pressure, sequential organ failure score, need for vasopressors, central venous pressure, leucocytes, hemoglobin, platelets, albumin, and mechanical ventilation (all P>0.05). The duration of ICU or NCU stay was 5 days in the experimental group compared with 7 days in the control group (P=0.009). Compared with the control group, the experimental group had shorter successful puncture time (4.0 vs. 6.0 min, P<0.001), higher first puncture success rate (93% vs. 71%, Ρ=0.023), and a lower incidence of complications (12.5% vs. 45.0%, P=0.001).Conclusions: For patients with sepsis in ICU, ultrasound-guided puncture is superior to blind manual puncture.