The results of the experimental analyses, described in Part 1, are here employed to build up an innovative numerical approach for the 1D modeling of combustion, cycle-by-cycle variations and knock of a high performance 12-cylinder spark-ignition engine. The whole engine is schematized in detail in a 1D framework simulation, developed in the GT-Power™ environment. Proper “in-house developed” sub-models are used to describe the combustion process, turbulence phenomenon, cycle-by-cycle variations (CCV) and knock occurrence. In particular, the knock onset is evaluated by a chemical kinetic scheme for a toluene reference fuel, able to detect the presence of auto-ignition reactions in the end-gas zone. In a first stage, the engine model is validated in terms of overall performance parameter and ensemble averaged pressure cycles, for various full and part load operating points and spark timings. Then, the correlation regarding the maximum in-cylinder pressure distribution developed in Part 1 is here applied to predict representative faster-then-average and slower-than-average cycles, miming the effects of the experimentally observed CCV. A proper knock index is introduced and evaluated with reference to the above faster-than-average cycle. An automatic procedure is implemented to identify the Knock Limited Spark Advance (KLSA), based on the same threshold level utilized in the experimental knock analysis of Part 1. The numerical and experimental KLSA presents an excellent agreement, denoting the accuracy of the proposed combustion and knock modeling.