Purpose: The purpose of this study was to determine whether there is a difference in the change in cross-sectional area (CSA) of the median nerve in patients undergoing carpal tunnel release (CTR) based on surgical technique and whether this change is associated with changes in patient-reported outcomes evaluated using the Carpal Tunnel Syndrome Assessment Questionnaire. Methods: Individuals with carpal tunnel syndrome were evaluated with ultrasound and the CTSAQ before and 6 weeks after surgery. Patients were eligible for inclusion if they underwent either a mini-open CTR (MOCTR) or endoscopic CTR (ECTR). A single surgeon performed all surgeries. Changes in median nerve CSA, Carpal Tunnel Syndrome Assessment Questionnaire scores, and their associated surgical technique (MOCTR vs ECTR) were analyzed. Results: A total of 77 patients were enrolled, 13 of whom were lost to follow-up, which left 64 for analysis. Of those, 42 patients underwent ECTR and 22 MOCTR. Mean age was 55 years; there were 52 women and 12 men. Mean changes in CSA for endoscopic and mini-open techniques from before to 6 weeks after surgery were -1.9 mm2 (95% confidence interval [CI], -1.1 to -2.7) and +0.6 mm2 (95% CI, -1.6 to 0.4), respectively. Mean Symptom Severity Scores improved after endoscopic and mini-open release by 1.7 (95% CI, 1.4-2.1) and 1.5 (95% CI, 1.2-1.9), respectively. Mean Functional Status Scores improved after endoscopic and mini-open release by 1.2 (95% CI, 0.9-1.9) and 0.7 (95% CI, 0.03-1.3), respectively. Conclusions: Patients undergoing ECTR demonstrated decreased median nerve CSA, whereas those undergoing MOCTR demonstrated increased median nerve CSA at 6 weeks. All patients undergoing surgical intervention demonstrated improvement in both Symptom Severity Scores and Functional Status Scores after surgery. Whereas both techniques successfully improve patient outcome scores, an increase in CSA after MOCTR may be seen in the initial postoperative period, potentially contributing to a slower short-term improvement in outcome in functional scores compared with ECTR. Type of study/level of evidence: Therapeutic IV.