Abstract: Objective To investigate the inhibitory effect of induced normal temperature control on the activation of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3) signaling pathway in severe multiple injury. Methods Total 90 patients with severe multiple injury admitted to the emergency department of our hospital from February 2018 to January 2019 were randomly divided into study group and control group, 45 patients with each group. The two groups were given mild hypothermia control and induced normal temperature control at the same time as the conventional treatment regimen. The mortality rate of the two groups was calculated. The acute physiology and chronic health evaluation(APACHE Ⅱ), Glasgow Coma Scale(GCS), the relative expression of NLRP3 and caspase-1 in peripheral blood mononuclear cells(PBMC), IL-1β and IL-18 levels in peripheral blood were compared before and after treatment. The incidence of adverse reactions during cooling and rewarming were analyzed. Results The mortality rate in the study group was 8.89% while that in the control group was 13.33%, there was no significant difference(P>0.05). After treatment, the APACHEⅡ score of the two groups decreased, and the study group was lower than the control group(all P<0.05). The GCS scores of the two groups increased after treatment, and the study group was higher than the control group(all P<0.05). After treatment, the relative expressions of NLRP3 and caspase-1 in PBMC, the levels of IL-1 β and IL-18 in peripheral blood of the two groups were decreased, and the levels of the study group were lower than those of the control group(all P<0.05). The incidence of adverse reactions in the study group(2.22%) was lower than that in the control group(17.78%), P<0.05. Conclusion Induced normal temperature control may promote the rehabilitation of patients with severe multiple injury by activating NLRP3-caspase-1-IL-1β/IL-18 signaling pathway, reduce adverse reactions during cooling and rewarming, and have high safety.