A novel process model simulating methanol production through pyrolysis oil gasification was developed, validated, then used to predict the effect of operating conditions on methanol production yield. The model comprised gasification, syngas post-treatment, and methanol synthesis units. The model was validated using experimental data from the literature, and the results obtained by the model were consistent with reference data. The simulation results revealed that gasification temperature has a significant impact on syngas composition. Indeed, rising temperature from 400 °C to 600 °C leads to higher syngas stoichiometric number (SN) value. Conversely, SN value decreases when the gasifier temperature is above 1000 °C. Moisture content in pyrolysis oil also affects both syngas composition and SN value; an increase in the first (from 10 to 30%) leads to an increase in SN value. The Rectisol unit deeply influences the syngas SN value and methanol yield, the best results being obtained with operating conditions of −20 °C and 40 bar. Increasing the operating temperature of the methanol synthesis unit from 150 °C to 250 °C leads to an increase in the yield of methanol production; the yield decreases beyond 250 °C. Although high pressures favor the methanol production yield, the operating pressure in the synthesis unit is limited at 50 bar for practical considerations (e.g., equipment price, equipment requirements, or operational risks).