Background: To evaluate novice and expert clinicians’ procedural confidence utilizing a blended learning mixed fidelity simulation model when applying a standardized ultrasound-guided central venous catheterization curriculum. Methods: Simulation-based education and ultrasound-guided central venous catheter insertion aims to provide facility-wide efficiencies and improves patient safety through interdisciplinary collaboration. The objective of this quality improvement research was to evaluate both novice (<50) and expert (>50) clinicians’ confidence across 100 ultrasound-guided central venous catheter insertion courses were performed at a mixture of teaching and non-teaching hospitals across 26 states within the United States between April 2015 and April 2016. A total of 1238 attendees completed a pre- and post-survey after attending a mixed method clinical simulation course. Attendees completed a 4-h online didactic education module followed by 4 h of hands-on clinical simulation stations (compliance/sterile technique, needling techniques, vascular ultrasound assessment, and experiential complication management). Results: The use of a standardized evidence-based ultrasound-guided central venous catheter curriculum improved confidence and application to required clinical tasks and knowledge across all interdisciplinary specialties, regardless of level of experience. Both physician and non-physician groups resulted in statistically significant results in both procedural compliance ( p < 0.001) and ultrasound skills ( p < 0.001). Conclusion: The use of a standardized clinical simulation curriculum enhanced all aspects of ultrasound-guided central venous catheter insertion skills, knowledge, and improved confidence for all clinician types. Self-reported complications were reported at significantly higher rates than previously published evidence, demonstrating the need for ongoing procedural competencies. While there are growing benefits for the role of simulation-based programs, further evaluation is needed to explore its effectiveness in changing the quality of clinical outcomes within the healthcare setting.