Objective To document changes in the median nerve cross‐sectional area (CSA) in the proximal carpal tunnel region after ultrasound (US)‐guided carpal tunnel release (CTR). Methods Prospective data were collected on 23 consecutive patients (37 wrists) treated with US‐guided CTR by the primary author using the same office‐based microinvasive technique. Ultrasound was used to measure the largest CSA of the median nerve in the proximal carpal tunnel region both preoperatively and postoperatively. The primary outcome measure was the change in the preoperative versus 6‐ to 10‐week postoperative median nerve CSA. Results The mean CSA of the median nerve decreased from 16.08 to 12.75 mm2 at 6 to 10 weeks after US‐guided CTR (P < .001). During the same period, the mean Boston Carpal Tunnel Questionnaire (BCTQ) symptom score decreased from 3.23 to 1.67 (P < .001), and mean BCTQ functional score decreased from 2.49 to 1.47 (P < .001), both exceeding minimal clinically important differences. Although the primary end point was the median nerve CSA at 6 to 10 weeks, statistically significant reductions in the median nerve CSA, as well as BCTQ scores, were also observed as early as 2 to 4 weeks after US‐guided CTR (median nerve CSA, 12.40 mm2; BCTQ symptom score, 2.00; BCTQ functional score, 1.75; all P ≤ .03). Conclusions To our knowledge, this investigation was the largest to date examining changes in the proximal median nerve CSA after US‐guided CTR. Statistically significant reductions in the proximal median nerve CSA were observed within 6 to 10 weeks after ultrasound‐guided CTR. These reductions were similar to those previously reported for open and endoscopic CTR and validate the ability of US‐guided CTR to relieve median nerve compression.