To compare the effect of goal-directed fluid resuscitation and bedside ultrasound-guided fluid resuscitation in patients with septic shock, and to evaluate the application value of bedside ultrasound in fluid resuscitation of patients with septic shock. Forty patients with septic shock admitted to department of critical care medicine of Affiliated Hospital of Nanjing University of Chinese Medicine from June 2018 to October 2019 were enrolled, and they were divided into early goal-directed therapy (EGDT) group and ultrasound group according to random number table, with 20 patients in each group. Bacterial cultures were routinely performed, and all patients received conventional treatments, such as anti-infection, nutritional support and organ support. All patients were given initial fluid resuscitation (30 mL/kg). The patients in the EGDT group continued to be given fluid resuscitation according to the guidelines (EGDT 6-hour target) after the initial fluid resuscitation. The patients in the ultrasound group were given follow-up fluid resuscitation based on bedside ultrasound inferior vena cava diameter and lung ultrasound B-line score after initial fluid resuscitation. The general data, main laboratory indexes and efficacy indexes of the two groups were compared, including 6-hour blood pressure achieved rate [mean arterial pressure (MAP) ≥ 65 mmHg (1 mmHg = 0.133 kPa) was defined as blood pressure reaching standard], 24-hour resuscitation fluid volume, 24-hour norepinephrine (NE) consumption, 24-hour oxygenation index (PaO2/FiO2) and 24-hour clearance of lactic acid (LCR) were compared between the two groups. The survival curve of intensive care unit (ICU) was drawn by Kaplan-Meier analysis. There was no significant difference in the gender, age, heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), underlying diseases, sequential organ failure assessment (SOFA) score, PaO2/FiO2, blood lactic acid (Lac), D-dimer, cardiac troponin I (cTnI), brain natriuretic peptide (BNP), total bilirubin (TBil) and serum creatinine (SCr) baselines at admission between the two groups. There was also no significant difference in the 6-hour target blood pressure achieved rate [65.0% (13/20) vs. 70.0% (14/20)], 24-hour total NE dosage [mg: 20.0 (10.0, 66.5) vs. 30.0 (10.5, 85.0)], 24-hour PaO2/FiO2 (mmHg: 274.6±123.8 vs. 243.1±124.0) or 24-hour LCR [9.1% (-34.5%, 58.0%) vs. 44.0% (-24.1%, 81.3%)] between the EGDT group and ultrasound group (all P > 0.05), but the 24-hour total fluid infusion in the ultrasound group was significantly less than that in the EGDT group (mL: 2 783.1±704.2 vs. 3 692.0±1 433.1, P < 0.05). The Kaplan-Meier survival curve showed that the cumulative survival rate of ICU between the two groups was not statistically significant (Log-Rank test: χ2 = 0.088, P = 0.767). Bedside ultrasound protocol combined inferior vena cava diameter with lung ultrasound B-line score can be used to guide fluid resuscitation in patients with septic shock, the total fluid infusion is decreased and the risk of oxygenation deterioration is reduced.