Introduction This study is to compare the efficacy of two different methods of nerve hydrodissection (HD), called short- and long-axis injection, for patients with mild-to-moderate carpal tunnel syndrome (CTS). Methods Forty-seven patients with mild-to-moderate CTS were enrolled in a prospective, randomized, single-blinded, controlled trial (6 months follow-up). With ultrasound guidance, patients in both groups (short-axis or long-axis groups) were injected with normal saline (5 mL per session). Assessments were performed before and 2 weeks after the injection, as well as at 1, 3, and 6 months post-intervention. The primary outcome measure was the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) score and secondary outcomes included the cross-sectional area of the median nerve and electrophysiological studies. Results Forty-four patients (21 wrists in the short-axis group and 23 wrists in the long-axis group) completed the study. Compared with the baseline, both groups showed improved BCTQ and cross-sectional area at all follow-up assessments (p<0.05). Moreover, the short-axis group had significant improvements in BCTQ-severity and BCTQ-function 1 month post-injection compared to the long-axis group (p = 0.031 and p = 0.023, respectively). Conclusion Both short- and long-axis HD were effective for patients with mild-to-moderate CTS; however, the short-axis HD conferred relatively better efficacy 1 month after the injection.