Introduction Although some research papers have suggested that smoking may increase mortality in patients with sepsis, no evidence has been produced in this regard. This systematic research evaluated the risk of death in patients with sepsis who were smokers to facilitate better clinical decision making. Material and Methods This is a systematic review registered in PROPERO (CRD42022296654). Searches were conducted to identify suitable studies from the databases of PubMed, Embase, Web of Science and the Cochrane Controlled Register of Trials from January 1980 to June 2021. Two independent reviewers screened the articles using keywords and extracted the data. The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of evidence. The primary endpoints included the mortality of patients with sepsis. Results Five studies involving 2694 participants were included in our study. Among the five included articles, three studies had an NOS score of 6, while the other two had an NOS score of 7. The results showed that a significantly higher risk of death was observed in smokers with sepsis compared with non-smokers with sepsis (hazard ratio, HR=1.62; 95% CI: 1.11–2.37, p=0.01). Among the patients followed for more than 2 months, the mortality rate of smokers was significantly higher (2.33 times) than that of non-smokers (HR=2.33; 95% CI: 1.83–2.96, p