Objective To compare the efficacy and complication between harmonic scalpel and traditional electric knife in open thyroidectomy. Methods A total of 160 thyroid disease patients who underwent open thyroidectomy in The Fifth Affiliated Hospital of Southern Medical University from February 2016 to January 2017, were collected and divided into harmonic scalpel group and traditional electric knife group randomly, each group enrolled 80 patients. The efficacy of thyroidectomy, postoperative pain, and complication between the 2 groups were compared and analyzed. Results Compared with the traditional electric knife group, the operation time, intraoperative blood loss, postoperative drainage volume, postoperative drainage time, length of incision, and hospital stay were all significantly lower in the harmonic scalpel group (P<0.05). The incidences hoarseness, wound bleeding, hypoparathyroidism, and total complication in the harmonic scalpel group were all lower than those of the traditional electric knife group (P<0.05). The pain scores after operation in the harmonic scalpel group were significant lower than corresponding pain scores of the traditional electric knife group (P<0.05). Conclusion The harmonic scalpel could effectively improve the efficacy of open thyroidectomy, reduce the pain degree and the incidence of complication in thyroid disease patients.