Objective Siwu mixture is derived from Siwu decoction, a classical Chinese medicine prescription, which is widely used in a variety of gynecological diseases. However, There are few studies on the therapeutic effect of Siwu mixture on primary dysmenorrhea. This study aims to further explain its therapeutic effect. Methods Sixty healthy animals were divided into four groups: the control group, model group, Siwu mixture group and Tongjingbao granule group. The primary dysmenorrhea mice model was induced by estrogen combined with oxytocin. After 3 days of adaptive feeding, mice were subcutaneously injected with estradiol benzoate 2 mg / kg for 10 days. The normal and the model group received the same dosage of distilled water from the 4th day. The Tongjingbao granule group was given 4 g / kg for 7 days. The Siwu mixture group was given 8 mL/ kg for 7 days. The analgesic effect of Siwu mixture was studied by writhing and the latency of writhing within 30 min after oxytocin injection. The serum contents of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined. ProstaglandinF_2α (PGF_2α ), interleukin-6 ( IL-6) and tumor necrosis factor-α (TNF-α) were measured in tissue homogenates by ELISA method. Uterine pathological sections were prepared to observe glandular hyperplasia and inflammatory cell infiltration, and the expression of cyclooxygenase-2 ( COX-2 ) was detected by immunohistochemistry. Results Compared with result in the control group, the body twisting in the model group increased (P<0. 01) and serum MDA increased (P<0. 01). Uterine tissue PGF_2α , TNF-α and IL-6 increased. In the model group, endometrial glands were dilated and papillary hyperplasia, interstitial edema, inflammatory cell proliferation and infiltration were observed; COX-2 expression was enhanced. The number of writhing events within 30 min in Tongjingbao granule group and Siwu mixture group decreased compared with controls (P<0. 05, P<0.01); the writhing latency in the Siwu mixture group increased (P<0.05) and the level of serum MDA in the positive drug group and Siwu mixture group decreased (P< 0.01). Conclusions Siwu mixture could significantly reduced the 30 min writhing times and prolonged the writhing latency of primary dysmenorrhea mice. The mechanism may be related to reducing the content of serum MDA and PGF_2α , TNF-α and IL-6 in uterine tissue and COX-2 expression are related to the improvement of histopathological changes.