Objective To conduct a clinical trial to investigate the effect of N‐acetyl cysteine (NAC), a non‐hormonal drug, on the volume of leiomyoma, the most common benign tumor in women. Methods This study is a randomized clinical trial, which was performed in Semnan, Iran. Eligible women who were diagnosed with uterine leiomyoma using vaginal ultrasound were randomly assigned to receive NAC or placebo for 12 weeks. The change in the volume of Leiomyoma was considered to be the main variable in the efficacy evaluation. Reduction in the leiomyoma volume was calculated after intervention and data were entered in SPSS version 23. Results Fifty individuals were enrolled in our study. 25 women received NAC, while 25 women took placebo. The mean volume of leiomyoma in group A was 5.71 cm3 and in group B was 6.56 cm3. The mean rate of volume reduction in the A and B groups was 25.25 % and 1.08 %, respectively, which demonstrated a significant difference between the two groups (P < 0.004). Conclusion Although this trial recommends the use of NAC as a non‐hormonal drug in the treatment of leiomyoma of the uterus, the possibility of treatment failure in controlling abnormal uterine bleeding cannot be ignored. Nevertheless, we can say it is feasible and effective in the reduction of leiomyoma volume.