Background: Carpal tunnel syndrome (CTS) presents a high burden on the healthcare system. However, no alternative treatments are provided during the waiting period. In addition, the incidence of severe patients with comorbidities is underestimated. The aim of this study was to determine whether nerve mechanical interface treatment improves the symptoms, function, and quality of life in pre-surgical CTS patients. Methods: A randomized controlled trial and intention-to-treat analysis were carried out. Forty-two patients with an electrodiagnosis of carpal tunnel syndrome, included on the surgery waiting list of a public healthcare system, were analyzed. The intervention group (n = 20) received a 45 min session/per week of instrument-assisted manual therapy (diacutaneous fibrolysis) for 3 weeks. The Boston Carpal Tunnel Questionnaire (BCTQ) was the primary outcome. The symptoms, mechanical threshold, grip strength, mechanosensitivity of the median nerve, quality of life, and patient satisfaction were included as secondary outcomes. The control group (n = 22) remained on the waiting list. Results: The intervention seems to be beneficial for the BCTQ score (function and symptoms scale), pain, and mechanosensitivity after treatment, at the 3 and 6 months follow-up (p < 0.05). Kinesiophobia was improved at 6 months (p = 0.043; η2 = 0.10) and the mechanical threshold at the 3-month follow-up (p = 0.048; η2 = 0.10). No differences were identified for grip strength. At 6 months, the intervention group patients were satisfied (100%), as opposed to the controls, who felt that they had experienced a worsening of their condition (50.1%). Conclusions: Nerve mechanical interface treatment improved the symptoms, function, and quality of life in pre-surgical CTS patients. One hundred percent of the treated patients, characterized as moderate and severe CTS with associated comorbidities, were satisfied.