ABSTRACT Objective Comparative analysis of the efficacy of three treatment methods for mild to moderate carpal tunnel syndrome (CTS): ultrasound-guided steroid hormone combined with mecobalamin for hydrodissection of the median nerve using 5% dextrose, and steroid hormone combined with mecobalamin for needle knife release of the transverse carpal ligament (TCL). Methods From July 2021 to July 2023, a total of 110 patients with mild to moderate carpal tunnel syndrome (CTS), clinically and electrophysiologically diagnosed at our hospital, were selected for this study, involving 134 affected wrists. Among them, 49 patients were assigned to the corticosteroid combined with mecobalamin treatment group (Group A), 52 patients to the corticosteroid and mecobalamin combined with needle knife release group (Group B), and 33 patients to the 5% dextrose treatment group (Group C). The Boston Carpal Tunnel Questionnaire scores (SSS, FSS), visual Analog Scale (VAS), numeric Rating Scale (NRS), cross-sectional area (CSA) of the median nerve at the proximal carpal tunnel, and the internal diameter (D) at the site of nerve compression were assessed before treatment and at 2 weeks, 1 month, and 3 months post-treatment. Results There were no statistically significant differences in preoperative SSS, FSS, VAS, and NRS scores among the three groups of CTS patients (P>0.05). After treatment, the overall clinical efficacy rates at 2 weeks, 1 month, and 3 months for Groups A, B, and C were 95.9%, 96.2%, and 93.9%, respectively, with no statistically significant differences among the groups (P>0.05). At 2 weeks, 1 month, and 3 months post-treatment, improvements were observed in SSS, FSS, VAS, and NRS scores for all three groups, with statistically significant differences (P<0.05); however, comparisons among the groups showed no statistically significant differences (P>0.05). At 2 weeks and 1 month post-treatment, there were no statistically significant differences in CSA and the internal diameter at the site of nerve compression among the three groups (P> 0.05). However, comparisons between the 3-month post-treatment and pre-treatment measurements revealed statistically significant differences (P<0.05). Conclusion All three ultrasound-guided treatment methods effectively improved the symptoms of mild to moderate carpal tunnel syndrome, with no significant differences in short-term efficacy.