Objectives: Esophageal high-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders, but it may be poorly tolerated and unsuccessful. We sought to evaluate a protocol for sedation and endoscopy-assisted (SEA) HRM in patients who previously failed standard HRM and assess patient perspectives towards it. Methods: Adult patients who previously failed HRM were prospectively enrolled. Under propofol sedation, an upper endoscopy was performed during which the HRM catheter was advanced under endoscopic visualization. If the catheter did not reach the stomach on its own, the endoscope itself or a snare was used to help it traverse the esophagogastric junction (EGJ). Results: Thirty patients participated (mean age 67.8, 70% female). The technical success of SEA-HRM was 100%. Twenty-two (73.3%) were diagnosed with a motility disorder including thirteen (43.3%) with achalasia. Eighteen (60%) had previously failed HRM due to discomfort/intolerance, while twelve (40%) failed due to catheter coiling in the esophagus. Subjects in the coiling group were more likely to need endoscopic assistance to traverse the EGJ (91.7% vs. 27.7%, p = 0.001) and have a motility disorder (100.0% vs. 55.6%, p = 0.010), including achalasia (75.0% vs. 22.2%, p = 0.004), compared to the discomfort/intolerance group. All patients preferred SEA-HRM and rated it higher than standard HRM (9.5 ± 1.3 vs. 1.9 ± 2.1, p = <0.001, on a scale of 1–10). Conclusions: SEA-HRM is a highly successful and well-tolerated option in patients who previously failed standard HRM. This should be the recommended approach in cases of failed HRM rather than secondary tests of esophageal motility.