Non-surgical techniques are usually hormonal in nature and include the use of drugs that turn off the production of estrogen from the ovaries (GnRH analogs). These medications are given for three to six months and induce a hypoestrogenic (low estrogen) state. When successful, they can shrink the fibroids by as much as 50%. Side effects of these drugs are similar to the symptoms of menopause and can include hot flashes, sleep disturbance, vaginal dryness, and mood changes. Bone loss leading to osteoporosis after long-term (6 to 12+ months) use is one complication. This is generally reversed after the treatment ends. These drugs may also be used as preoperative treatment for large leiomyoma to shrink them in order to make the operation less difficult and reduce surgical risk.

Mifepristone (RU-486) is an antiprogestin drug that can shrink fibroids to an extent comparable to treatment with the GnRH analogs. This drug is also used to terminate early pregnancy. Treatment with mifepristone also reduced the bleeding associated with fibroids, but this treatment can be associated with adverse side effects such as overgrowth (hyperplasia) of the endometrium (uterine lining). Mifepristone is not approved by the US Food and Drug Administration (FDA) for the treatment of uterine leiomyomas, and the required dosages (different from those used for termination of early pregnancy) have not been determined.

Danazol (Danocrine) is an androgenic steroid hormone that has been used to reduce bleeding in women with fibroids, since this drug causes menstruation to cease. However, danazol does not appear to shrink the size of fibroids. Danazol is also associated with significant side effects, including weight gain, muscle cramps, decreased breast size, acne, hirsutism (inappropriate hair growth), oily skin, mood changes, depression, decreased high density lipoprotein (HDL or 'good cholesterol') levels, and increased liver enzyme levels.

The administration of raloxifene (Evista), a drug used to prevent and treat osteoporosis in postmenopausal women, has been shown to decrease the size of fibroids in postmenopausal women, but results with this therapy in premenopausal women have been conflicting.

Low dose formulations of oral contraceptives are also sometimes given to treat the abnormal bleeding associated with fibroids, but these do not shrink the fibroids themselves.