Background Hospitalized neonates require reliable vascular access for life-saving care. The costs associated with their clinical management, and which aspects of care these costs are attributable to, is not well-known. Objective To estimate the economic burden of vascular access care in neonates in the United States and to break down the attribution of costs therein by establishing an economic model of standard care. Design and methods A four step, mixed-methods study was used to determine and analyse an appropriate economic model for neonatal umbilical venous catheter and peripherally inserted central catheter insertion from the payer’s perspective in the US. An initial model was developed based on a purposive literature search. Secondly, initial face validity of the model was assessed with input from North American clinical experts identified to have appropriate expertise (n = 13 for the care of peripherally inserted central catheters and n = 12 for the care of umbilical venous catheters).Thirdly, a face-to-face meeting with the same clinical experts was undertaken to ensure the model structure and inputs accurately reflected clinical practice. Lastly, the finalised model was analysed. Results Feedback from the survey and focus group on model structure, resource usage and costings were incorporated to create decision-tree models for both umbilical venous catheter and peripherally inserted central catheter care. High variability between the opinions of clinicians was noted, which was incorporated into the sensitivity analyses. The umbilical venous catheter base-case expected cost was $390.24 per patient, with an average of 0.04 complications expected per-patient. The peripherally inserted central catheter model base-case expected cost was $1517.83 per patient, with an average of 0.1 complications per-patient. In the umbilical venous catheter model $82.73 of cost was attributable to malposition and $46.36 to migration. In the peripherally inserted central catheter model, $75.58 was attributable to malposition and $755.14 to migration. Deterministic sensitivity analysis indicated that the strongest driver of costs was catheter dwell time (umbilical venous catheter lower: $245.55, umbilical venous catheter upper: $578.77, peripherally inserted central catheter lower: $1263.40, peripherally inserted central catheter upper: $1771.74), followed by probability of migration (umbilical venous catheter lower: $343.91, umbilical venous catheter upper: $439.14, peripherally inserted central catheter lower: $1329.04, peripherally inserted central catheter upper: $1733.58) in both models. Conclusions The migration and malposition of peripherally inserted central catheters and umbilical venous catheters has significant costs and consequences. These should be targeted for evidence-based and innovative solutions to improve neonatal vascular access care.