In this article, a model predictive self-tuning regulator (MP-STR) with adaptive variable functioning (AVF) is designed for fuel injection feedback control. Proper control of wall-wetting effects in transients is a matter of great challenge in port fuel injection spark-ignition (SI) engines. A self-tuning regulator is employed to address both parametric and unstructured uncertainties, but in a predictive practice, in order to achieve optimal behavior, particularly in transient phases. Additionally, it is applied with AVF to maintain the control system work in real time, that is, at low speeds with longer computation time available, the MP-STR is wholly applied, yet at higher speeds with lower computation time in hand, a lighter controller, for instance, an offline adaptive controller including the predictive compensator with offline parameters, coupled with a simple proportional integral (PI) controller, is employed. As will be seen, the control system is fully capable of maintaining the output close to the desired value, much more preferable than that of the conventional controller.