Objective To determine the effects of dexmedetomidine and propofol on inflammatory response and S100β protein in patients with sepsis associated encephalopathy (SAE). Methods A total of 50 SAE patients undergoing mechanical ventilation admitted to the intensive care unit (ICU) of our hospital from July 2017 to December 2018 were prospectively enrolled in this study. They were randomly divided into propofol group and dexmedetomidine group, 25 cases in each group. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and central nervous system specific protein S100β at 1 (T1), 12 (T2) and 24 h (T3), and 3 d (T4) after the treatment, incidence of adverse reactions, mortality and length of ICU stay were compared between the 2 groups. SPSS statictis 20.0 was used to analyze the data. Student′s t test or Chi-square test was employed for intergroup comparison. Results The levels of TNF-α at T2, T3 and T4 [(17.83±2.09) vs (19.96±2.65)ng/L, (14.95±3.37) vs (18.83±4.46)ng/L, (8.62±3.07) vs(17.75±5.06)ng/L], those of S100β [(0.69±0.05) vs (0.61±0.04)μg/L, (0.62±0.03) vs (0.55±0.03)μg/L, (0.56±0.02) vs (0.42±0.01)μg/L] at the same time points, and those of IL-6 [(340.71±10.37) vs (390.89±12.26)ng/L, (240.62±10.54) vs (331.15±12.64)ng/L] at T3 and T4 were significantly lower in the dexmedetomidine group than the propofol group (P<0.05). There were 1 case of respiratory depression, 4 cases of bradycardia and 2 cases of hypotension in the dexmedetomidine group, and 2 cases of respiratory depression, 3 cases of bradycardia, and 4 cases of hypotension in the propofol group. No statistical difference was seen in the incidence of adverse reactions between the 2 groups [28%(7/25) vs 36%(9/25), P>0.05]. In the dexmedetomidine group, 4 patients died, and the length of ICU stay was (13.19±2.26)d. For the propofol group, 2 patients died, and ICU length was (13.07±2.16)d. There was no differences in the mortality and ICU length between the 2 groups (P>0.05). Conclusion Dexmedetomidine can attenuate inflammatory response to some extent and achieve ideal sedative effect in SAE patients.