Background/Objectives: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with Lumen-Apposing Metal Stent (LAMS) is an established option for high-surgical-risk patients, with high technical and clinical success. Indications include acute cholecystitis and palliation of jaundice in malignant distal biliary obstruction (MDBO). Both trans-gastric and trans-duodenal approaches are used, but the optimal route remains debated. The aim of the study was to compare trans-gastric and trans-duodenal access in terms of technical success, adverse events, readmissions, and reinterventions. Methods: We implemented a single-centre retrospective study of consecutive EUS-GBD procedures with LAMS at a tertiary endoscopy unit (January 2020–January 2026). Demographic, clinical, and procedural data were analyzed using appropriate statistical tests. Results: Seventy patients were included (51.4% male; mean age 77 ± 12 years). Indications were acute cholecystitis (64.3%) and MDBO (35.7%). Trans-gastric access was used in 48.5% of cases. A Hot-Axios LAMS was deployed in 77.2% of cases, mostly >10 mm. Technical success was achieved in 98.5% of cases. Naso-cystic drainage (NCD) was used through the LAMS in 47.1% of patients, while a double pig-tail plastic stent was used in 7.2% of patients. Adverse events were rare (1.4% misdeployment). LAMS obstruction occurred in 10% of patients, with reintervention required in 12.8% of patients. No differences were found between access routes in indication, technical success, LAMS type/size, or adjunctive drainage. However, trans-gastric access was associated with a higher reintervention rate (p = 0.01). Conclusions: EUS-GBD is a safe and effective procedure. While both approaches are comparable in most outcomes, the trans-gastric route may carry a higher risk of reintervention and should be avoided when alternative access is feasible.