Objective To explore the influence of external fixator combined with antibiotic-impregnated calcium sulfate on postoperative infection and bone healing in patients with open tibia and fibula fractures. Methods A total of 83 patients with open tibia and fibula fractures admitted to the First Affiliated Hospital of Hainan Medical College from June 2017 to June 2020 were selected, and according to the throwing method randomly divided into observation group (n=41) and control group (n=42). Patients in the control group were treated with external fixator, and those in the observation group were treated with external fixator combined with antibiotic-impregnated calcium sulfate. The bone healing (including complete weight bearing time, swelling elimination time, external fixator removal time, bone healing time), knee function (HSS score), ankle function (AOFAS score), quality of life, and incidence of complications were compared between the two groups. Results There was no statistically significant difference in the general data between the two groups (P>0.05). The complete weight bearing time, swelling elimination time, external fixator removal time, and bone healing time in observation group were shorter than in control group (P<0.05). There was no statistically significant difference in HSS score, AOFAS score and SF-36 score between the two groups before treatment (P>0.05). After treatment, the HSS scores and AOFAS scores of the two groups increased, and the observation group had higher scores than the control group (P<0.05). The SF-36 scores of the two groups increased, and the scores for energy, general health and physiological function in observation group were higher than in control group (P<0.05). There was no statistically significant difference in the incidence of malunion, nonunion and decreased muscle strength between the two groups (P>0.05), but the incidence of wound infection was lower in observation group than in control group (P<0.05). Conclusion External fixator combined with antibiotic-impregnated calcium sulfate is effective in treatment of patients with open tibia and fibula fractures, which can significantly reduce the postoperative infection rate and accelerate bone healing.