Background: Carpal tunnel syndrome is the most common entrapment neuropathy in the upper extremity, making it essential to assess the effectiveness of various physiotherapy treatments. Purpose: This study aimed to determine the clinical and electrodiagnostic improvement in mild-to-moderate carpal tunnel syndrome patients through manual lymphatic drainage (MLD) versus an orthosis alone. Study Design: This is a prospective randomized controlled study. Methods: The sample consisted of a total of 36 patients who met the inclusion criteria. Experimental group received MLD and orthosis, and the control group received only orthosis. The patients were evaluated with electrodiagnostic tests, Visual Analog Scale, algometer measurements (pressure pain threshold), Boston Carpal Tunnel Syndrome Questionnaire before and after treatment. Evaluations were made before and after treatment (4 weeks later). Results: Boston Carpal Tunnel Syndrome Questionnaire scores improved significantly with both treatment methods in both the experimental (p < 0.001, d = 2.0) and control groups (p < 0.001, d = 1.5). The pressure pain threshold significantly increased in the experimental group at the level of the transverse carpal ligament (p = 0.02, d = 0.86, 95% Confidence Interval (CI) = −0.08 to 1.2). At the distal radioulnar joint and extensor digitorum communis muscle levels, the pressure pain threshold similarly increased for two groups after treatment (p = 0.65, d = 0.31, 95% CI = −0.44 to 1.2), but the post-treatment increase in the experimental group was significant (p = 0.007, d = 0.31). In the experimental group, motor velocity (p = 0.001, d = 0.98), amplitude (p = 0.002, d = 1.5), and latency (p = 0.002, d = 0.60) and sensory velocity (p = 0.03, d = 0.91) and latency (p = 0.001, d = 1.2) significantly improved, while in the control group, there was a significant change only in motor velocity and amplitude (p = 0.047, d = 0.59). The post-treatment sensory improvement was significantly higher in the experimental group (p = 0.01, d = 0.81, 95% CI = −0.78 to −0.49). Conclusions: MLD significantly improved sensory conduction velocity, amplitude, and latency of the median nerve. Additionally, MLD and orthosis increased the pain pressure threshold and led to functional improvement. Clinical trial registration: This is listed with study ID: NCT05394870