With global estimates of 15 million cases of sepsis annually, together with a 24% in-hospital mortality rate, this condition comes at a high cost to both the patient and to the health services delivering care. This translational research determined the cost-effectiveness of state-wide implementation of a whole of hospital Sepsis Pathway in reducing mortality and/or hospital admission costs from a healthcare sector perspective, and report the cost of implementation over 12-months. A non-randomised stepped wedge cluster implementation study design was used to implement an existing Sepsis Pathway (“Think sepsis. Act fast”) across 10 of Victoria’s public health services, comprising 23 hospitals, which provide hospital care to 63% of the State’s population, or 15% of the Australian population. The pathway utilised a nurse led model with early warning and severity criteria, and actions to be initiated within 60 minutes of sepsis recognition. Pathway elements included oxygen administration; blood cultures (x2); venous blood lactate; fluid resuscitation; intravenous antibiotics, and increased monitoring. At baseline there were 876 participants (392 female (44.7%), mean 68.4 years); and during the intervention, there were 1,476 participants (684 female (46.3%), mean 66.8 years). Mortality significantly reduced from 11.4% (100/876) at baseline to 5.8% (85/1,476) during implementation (p>0.001). Respectively, at baseline and intervention the average length of stay was 9.1 (SD 10.3) and 6.2 (SD 7.9) days, and cost was $AUD22,107 (SD $26,937) and $14,203 (SD $17,611) per patient, with a significant 2.9 day reduction in length of stay (-2.9; 95%CI -3.7 to -2.2, p<0.01) and $7,904 reduction in cost (-$7,904; 95%CI -$9,707 to -$6,100, p<0.01). The Sepsis Pathway was a dominant cost-effective intervention due to reduced cost and reduced mortality. Cost of implementation was $1,845,230. In conclusion, a well-resourced state-wide Sepsis Pathway implementation initiative can save lives and dramatically reduce the health service cost per admission.