(1) Background: Abnormal liver function tests are commonly encountered in clinical practice, often leading to additional workup to determine the underlying etiology of these abnormal laboratory studies. As part of this evaluation, if less invasive imaging studies are performed and are without evidence of biliary obstruction, liver biopsy may be performed, and the finding of large duct obstruction on liver biopsy is commonly encountered. The utility of endoscopic retrograde cholangiopancreatography (ERCP) for evaluation and management of possible biliary obstruction in patients with large duct obstruction on liver biopsy has not been studied to date. (2) Methods: To assess the utility of ERCP in patients with large bile duct obstruction on liver biopsy, we retrospectively evaluated patients with large duct obstruction on liver biopsy from 2010–2019 at our tertiary care and transplant center. Demographic and clinical characteristics were evaluated for all patients, with sub-group analysis for patients who underwent ERCP and those who had intervenable findings at the time of ERCP. Descriptive statistics with proportions, means, and standard deviations were performed for demographics and clinical variables using absolute standardized difference. (3) Results: During the study period, 189 liver biopsies with evidence of large duct obstruction were performed. After exclusion criteria were applied, 166 unique patients were eligible for the study. Ninety-one patients with evidence of large duct obstruction on liver biopsy underwent ERCP and 75 did not. Of the 91 patients who underwent ERCP, 76 patients (84%) had an intervenable finding at ERCP. Patients who underwent ERCP were overall more likely to have had a liver transplant (65% ASD 0.63), have previously undergone cholecystectomy (80%, ASD 0.56), and be immunocompromised (80%, ASD 0.56). (4) Conclusions: ERCP is high yield when large duct obstruction is apparent on liver biopsy, with the majority of patients (84%) who undergo ERCP in this clinical context having a biliary finding necessitating therapeutic endoscopic intervention.