Knock is a major impediment to achieving higher efficiency in Spark-Ignition (SI) engines. The recent trends of boosting, downsizing and downspeeding have exacerbated this issue by driving engines toward higher power density and higher load duty cycles. Apart from the engine operating conditions, fuel anti-knock quality is a major determinant of the knocking tendency in engines, as quantified by its octane number (ON). The ON of a fuel is based on an octane scale which is defined according to the standard octane rating methods for Research Octane Number (RON) and Motor Octane Number (MON). These tests are performed in a single cylinder Cooperative Fuel Research (CFR) engine. In the present work, a numerical approach was developed based on multidimensional computational fluid dynamics (CFD) to predict knocking combustion in a CFR engine. The G-equation model was employed to track the propagation of the turbulent flame front and a multi-zone model based on temperature and equivalence ratio was used to capture auto-ignition in the endgas ahead of the flame front. Furthermore, a novel methodology was developed wherein a lookup table generated from a chemical kinetic mechanism could be employed to provide laminar flame speed as an input to the G-equation model, instead of using empirical correlations. To account for fuel chemistry effects accurately and lower the computational cost, a compact 121-species primary reference fuel (PRF) skeletal mechanism was developed from a more detailed gasoline surrogate mechanism using the directed relation graph assisted sensitivity analysis (DRGASA) reduction technique. Extensive validation of the skeletal mechanism was performed against experimental data available in the literature for both homogeneous ignition delay and laminar flame speed. The skeletal mechanism was used to generate the lookup tables for laminar flame speed as a function of pressure, temperature and equivalence ratio. The engine CFD model incorporating the skeletal mechanism was employed to perform numerical simulations under RON and MON conditions for different PRFs. Parametric tests were conducted at different compression ratios and the predicted values of critical compression ratio (at knock onset), delineating the boundary between “no knock” and “knock”, were found to be in good agreement with the available experimental data. The virtual CFR engine model was, therefore, demonstrated to be capable of adequately capturing the sensitivity of knock propensity to fuel chemistry.