Background: Critically ill patients are often hyperglycemic and insulin resistant, as well as highly dynamic. Tight glucose control has been shown to significantly reduce mortality in critical care. A physiological model of the glucose–insulin regulatory system is improved and used to develop an adaptive control protocol utilizing both nutritional and insulin inputs to control hyperglycemia. The approach is clinically verified in a critical care patient cohort. Methods: A simple two- compartment model for glucose rate of appearance in plasma due to stepwise enteral glucose fluxes is developed and incorporated into a previously validated system model. A control protocol modulating intravenous insulin infusion and bolus, with an enteral feed rate, is developed, enabling tight and predictive glycemic regulation to preset targets. The control protocol is adaptive to patient time-variant effective insulin resistance. The model and protocol are verified in seven 10-h and one 24-h proof-of-concept clinical trials. Ethics approval was granted by the Canterbury Ethics Committee. Results: Insulin requirements varied widely following acute changes in patient physiology. The algorithm developed successfully adapted to patient metabolic status and insulin sensitivity, achieving an average target acquisition error of 9.3% with 90.7% of all targets achieved within ±20%. Prediction errors may not be distinguishable from sensor measurement errors. Large errors (>20%) are attributable to highly dynamic and unpredictable changes in patient condition. Conclusions: Tight, targeted stepwise regulation was exhibited in all trials. Overall, tight glycemic regulation is achieved in a broad critical care cohort with optimized insulin and nutrition delivery, effectively managing glycemia even with high effective insulin resistance.