Bacterial healthcare-associated infections (HAIs) are a substantial source of global morbidity and mortality. The estimated cost associated with HAIs ranges from $35 to $45 billion in the USA alone. The costs and accessibility of whole genome sequencing (WGS) of bacteria and the lack of sufficiently accurate, high-resolution, scalable and accessible analysis for strain identification are being addressed. Thus, it is timely to determine the economic viability and impact of routine diagnostic bacterial genomics. The aim of this study was to model the economic impact of a WGS surveillance system that proactively detects and directs interventions for nosocomial infections and outbreaks compared to the current standard of care, without WGS. Using a synthesis of published models, inputs from national statistics, and peer-reviewed articles, the economic impacts of conducting a WGS-led surveillance system addressing the 11 most common nosocomial pathogen groups in England and the USA were modelled. This was followed by a series of sensitivity analyses. England was used to establish the baseline model because of the greater availability of underpinning data, and this was then modified using USA-specific parameters where available. The model for the NHS in England shows bacterial HAIs currently cost the NHS around £3 billion. WGS-based surveillance delivery is predicted to cost £61.1 million associated with the prevention of 74 408 HAIs and 1257 deaths. The net cost saving was £478.3 million, of which £65.8 million were from directly incurred savings (antibiotics, consumables, etc.) and £412.5 million from opportunity cost savings due to re-allocation of hospital beds and healthcare professionals. The USA model indicates that the bacterial HAI care baseline costs are around $18.3 billion. WGS surveillance costs $169.2 million, and resulted in a net saving of ca.$3.2 billion, while preventing 169 260 HAIs and 4862 deaths. From a ‘return on investment’ perspective, the model predicts a return to the hospitals of £7.83 per £1 invested in diagnostic WGS in the UK, and US$18.74 per $1 in the USA. Sensitivity analyses show that substantial savings are retained when inputs to the model are varied within a wide range of upper and lower limits. Modelling a proactive WGS system addressing HAI pathogens shows significant improvement in morbidity and mortality while simultaneously achieving substantial savings to healthcare facilities that more than offset the cost of implementing diagnostic genomics surveillance.