To investigate the effect of Guizhi fuling decoction combined with norethisterone tablets for treating women with endometriosis, and to study it influence on their serum COX-2 and macrophage movement inhibition factor (MIF) levels. Methods: 132 women with endometriosis were randomly divided into three groups from January 2017 to February 2018. The women in group A were treated with norethindrone tablet, the women in group B were treated with Guizhi fuling decoction oral, and the women in group C were treated with Guizhi fuling decoction oral combined with norethindrone tablet. The treatment efficacy, adverse effects, VAS score, quality of life, and serum COX-2 and MIF levels of women were compared among the three groups. Results: The total effective rate of women in group C was 95.5%, which was significant higher than that (84.1%) of women in group A and that (86.4%) of women in group B. The pain VAS score, chronic pelvic pain score, intercourse pain score, and the serum COX-2 and MIF levels of women in group C were 1.12±0.50 points, 1.31±0.37 points, 1.12±0.21 points, and 24.54 ± 4.32 ng/ml and 10.98 ± 3.23 ng/ml, which were significant lower than those of women in group A and B. The quality of life score of women in group C was 94.2±5.4 points, which was the highest in the three groups (all P<0.05). The adverse reactions of women in group C was 4.6%, which had no difference from that of women in other two groups (P>0.05). Conclusion: Guizhi fuling decoction combined with norethisterone tablets for treating women with endometriosis can improve their clinical symptoms of the patients quickly, reduce their pain of dysmenorrhea and sexual life, and improve their quality of life, which can significantly reduce their serum COX-2 and MIF levels without increasing the adverse reaction.