Recently, there has been a renewed interest in traditional medicine for carpal tunnel syndrome (CTS). Curcumin has been reported as an agent with antioxidant, anti-inflammatory, analgesic, and neuroprotective attributes. This study is one of the first investigations to assess the effect of curcumin gel on CTS. This study is a prospective, 8-week, randomized, placebo-controlled, parallel-group clinical trial. A total of 70 patients with CTS were analyzed. The intervention group (n = 35) received a topical curcumin gel and a night wrist splint and the control group (n = 35) received a placebo gel and a night wrist splint for 8 weeks. The primary outcome was the assessment of the symptom severity scale (SSS) and functional status scale (FSS) of the participants using the Boston Carpal Tunnel Questionnaire (BCTQ) after 8 weeks. In addition, all participants were evaluated by electrodiagnostic (EDX) test at baseline and after 8 weeks. The mean scores of SSS demonstrated a significant decrease in the curcumin group compared to the placebo group; P-value= 0.021. The mean change score of SSS after the intervention was 12.45 ± 8.18 in curcumin and 3.28 ± 7.06 in the placebo group; P-value = 0.0001 and the mean change score of FSS were 6.24 ± 4.91 and 2.31 ± 4.95 in curcumin and placebo groups, respectively; P-value = 0.002. However, the EDX study showed no significant changes in both groups. It seems that curcumin gel could be effective in the improvement of the symptom severity and daily activity of patients with CTS.