Objective To discuss the clinical effects of different energy densities of enteral nutrition (EN) preparations on mechanical ventilation (MV) patients with acute severe traumatic brain injury (sTBI). Methods Sixty MV patients with acute sTBI admitted to the Department of Critical Care Medicine of Hangzhou Xiaoshan District First People's Hospital from July 2015 to December 2017 were divided into two groups according to different energy densities of nutritional preparations. Thirty patients of the control group were given nasal feeding with standard energy density EN (energy density 3.35 - 4.19 kJ/mL) and 30 patients of the observation group were given nasal feeding with relatively higher energy density (energy density 5.44 - 6.28 kJ/mL). The indexes of nutritional status between the two groups before and after treatment were compared: including prealbumin (PA), albumin (Alb), globulin (Glo), hemoglobin (Hb), 5-day and 1-week heat calorie compliance rates of reaching target calories, MV time and incidence of complications. Results There were no statistically significant differences in nutritional indicators before treatment between the two groups (all P > 0.05). The compliance rates of reaching target calories of the observation group on the 5 and 7 days after treatment were significantly higher than those in the control group [5 days: 66.67% (20/30) vs. 50.00% (15/30), 1 week: 81.33% (25/30) vs. 70.00% (21/30), both P < 0.05], and the MV time was significantly lower than that in the control group (hours: 92.48±12.04 vs. 128.88±16.29, P < 0.05); the levels of PA, Alb, Hb, Glo were significantly higher in the observation group than those in control group on the 21st day after treatment [PA (g/L): 0.28±0.11 vs. 0.15±0.04, Alb (g/L): 36.52±5.79 vs. 29.63±2.74, Hb (g/L): 92.40±9.50 vs. 81.10±8.60, Glo (g/L): 24.42±1.73 vs. 18.19±3.59, all P < 0.05]. Complications: the total incidence of abdominal distension, diarrhea and constipation of the observation group was 36.6% (11/30), while that of the control group was 66.7% (20/30), the difference between the two groups being statistically significant (P < 0.05). Conclusion High energy density enteral nutrition can improve the nutritional status of the organisms of MV patients with acute sTBI, reduce the time of MV and the incidence of complications, thus it is worthy to be widely applied clinically.