Background: Experience from first-generation closed-loop (CL) systems informs refinements to enhance glucose control and user acceptance. A next-generation prototype enhanced-hybrid CL (E-HCL) system incorporates iterative changes to the Medtronic MiniMed 670G CL system, including automated correction boluses, lower target glucose level, and user enhancements. The aim was to explore safety, system performance, and glucose control using E-HCL in adults with type 1 diabetes. Methods: Twelve adults underwent this first in-human feasibility study. After a 1-week run-in using open-loop (OL), E-HCL was activated at the start of a supervised 1-week hotel phase, followed by 3 weeks free living at home. Supervised challenges included two meal interventions (unannounced and late meal bolus) and a sensor calibration intervention. Primary outcome was sensor glucose time-in-range (TIR); OL run-in and E-HCL at home were compared by Wilcoxon signed-rank test. Results: Twelve adults (seven men; median [interquartile range] age 48 [39, 57] years; HbA1c 6.8 [6.2, 7.2]%, 51 [44, 55] mmol/mol; diabetes duration 31 [13, 41] years) completed the protocol. E-HCL resulted in greater TIR (85.3 [79.4, 88.4]% vs. 75.0 [66.6, 83.7]%, P = 0.003) and lower mean sensor glucose (123.0 [119.3, 129.6] mg/dL vs. 143.5 [135.8, 154.5] mg/dL, P = 0.002) than OL. Time spent <70 mg/dL increased using E-HCL (4.4 [3.3, 6.1]% vs. 3.0 [1.8, 3.8]%, P = 0.02) with no difference in time <54 mg/dL (P = 0.64). Time in CL was 99.98 [99.0, 100.0]%. All participants were satisfied using E-HCL. Conclusions: In adults with well-controlled HbA1c levels, a prototype E-HCL resulted in high TIR, few CL exits, and positive user experiences at the expense of increased hypoglycemia (<70 mg/dL). E-HCL represents a positive step in the journey toward optimizing glucose control in people living with type 1 diabetes.